Organic compounds

ABSTRACT

The present invention provides a compound of formula I; 
     
       
         
         
             
             
         
       
     
     a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

BACKGROUND OF THE INVENTION

The mineralocorticoid hormone aldosterone is produced by the adrenalgland and acts on the distal tubules and collecting ducts of the kidneyto increase reabsorption of ions and water in the kidney. Aldosteronecauses conservation of sodium, secretion of potassium, increased waterretention, and increased blood pressure.

Aldosterone has been implicated in the pathogenesis of cardiovasculardiseases such as hypertension and heart failure. In clinical trials,treatment with the nonselective mineralocorticoid receptor antagonist(MRA) spironolactone or the selective MRA eplerenone significantlyreduced morbidity and mortality among patients with heart failure ormyocardial infarction already taking an angiotensin-converting enzymeinhibitor or a β-blocker. However, significant side effects such asgynecomastia and impotence were observed in male patients receivingspironolactone while hyperkalemia was seen in patients taking eitherdrug.

SUMMARY OF THE INVENTION

The invention pertains to the compounds, methods for using them, anduses thereof as described herein. Examples of compounds of the inventioninclude the compounds according to any one of Formulae I-VIII, orpharmaceutically acceptable salt thereof, and the compounds of theexamples.

The invention therefore provides a compound of the Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is CH₂, O, S or —NR¹;

each R¹ are independently C₁₋₇alkyl or C₃₋₈cycloalkyl;

each of R² and R⁶ are independently hydrogen, halogen, cyano, C₁₋₇alkyl,hydroxy-C₁₋₇alkyl, —OR⁷, C₃₋₈cycloalkyl, halo-C₁₋₇alkyl or—CH₂—NR⁸—SO₂R¹⁰;

R³ and R⁴ are independently hydrogen, halogen or cyano;

R⁵ is hydrogen, C₁₋₇alkyl, halogen, cyano, hydroxy, hydroxy-C₁₋₇alkyl,hydroxy-C₃₋₈cycloalkylalkyl, C₁₋₇alkoxy-C₃₋₈alkyl, —OR⁷, C₆₋₁₀aryl,heteroaryl, heterocyclyl, C₃₋₈cycloalkyl, halo-C₁₋₇alkyl, —NR⁸R⁹,—CH₂—NR⁸—C(O)NR⁸R⁹, —CH₂—NR⁸—SO₂—R¹⁰, —C(O)—R¹⁰, —SO₂R¹⁰, —C(O)—NR⁸R⁹,—SO₂—NR⁸R⁹, —NR⁸C(O)—R¹⁰, —CH₂CN or —NR⁸—SO₂R¹⁰;

R⁷ is C₁₋₇alkyl, C₃₋₈cycloalkyl-C₁₋₇alkyl, heterocyclyl-C₁₋₇alkyl,C₆₋₁₀aryl-C₁₋₇alkyl, heteroaryl-C₁₋₇alkyl or —C(O)—R¹⁰; in whichC₆₋₁₀aryl, heteroaryl, C₁₋₇alkyl, heterocyclyl and C₃₋₈cycloalkyl areoptionally substituted with C₁₋₇alkoxy, halo, halo-C₃₋₈alkoxy,C₁₋₇alkyl, OH or halo-C₁₋₇alkyl;

each of R⁸, R⁹ are independently hydrogen, C₁₋₇alkyl, halo-C₁₋₇alkyl,C₆₋₁₀aryl-C₁₋₇alkyl or heterocyclyl; or R⁸ and R⁹ can form together withthe nitrogen atom to which they are attached a 5- or 6-membered ringheterocyclyl, wherein said heterocyclyl optionally contain an additionalheteroatom selected from N, O or S and is optionally substituted withC₁₋₇alkyl; and

R¹⁰ is hydrogen, C₁₋₇alkyl, halo C₁₋₇alkyl, C₆₋₁₀aryl-C₁₋₇alkyl, —NR⁸R⁹,or heterocyclyl;

wherein each heteroaryl is a mono- or bicyclic aromatic moietycomprising 5-10 ring atoms selected from carbon atoms and 1 to 5heteroatoms, and

each heterocyclyl is a mono- or bicyclic saturated or partiallysaturated but non-aromatic moiety comprising 4-10 ring ring atomsselected from carbon atoms and 1 to 5 heteroatoms; and each heteroatomsbeing O, N or S, and with the proviso that when R⁵ is halogen orhydrogen than at least one of R² and R⁶ is other than H.

In another embodiment, the invention pertains, at least in part, to amethod for treating a disorder or disease mediated by aldosteronesynthase and/or 11-beta hydroxylase (CYP11B1) in a subject byadministering to the subject a therapeutically effective amount of acompound according to anyone of Formulae I-VIII, or a pharmaceuticallyacceptable salt thereof, such that the disorder or disease mediated byaldosterone synthase and/or CYP11B1 in the subject is treated.

In yet another embodiment, the invention pertains, at least in part, toa method for treating a subject for hypokalemia, hypertension, Conn'sdisease, renal failure, in particular, chronic renal failure,restenosis, atherosclerosis, syndrome X, obesity, nephropathy,post-myocardial infarction, coronary heart diseases, increased formationof collagen, fibrosis and remodeling following hypertension andendothelial dysfunction, cardiovascular diseases, renal dysfunction,liver diseases, cerebrovascular diseases, vascular diseases,retinopathy, neuropathy, insulinopathy, edema, endothelial dysfunction,baroreceptor dysfunction, migraine headaches, heart failure such ascongestive heart failure, arrhythmia, diastolic dysfunction, leftventricular diastolic dysfunction, diastolic heart failure, impaireddiastolic filling, systolic dysfunction, ischemia, hypertrophiccardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis,impaired arterial compliance, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, decreasedejection fraction, cardiac lesions, vascular wall hypertrophy,endothelial thickening, or fibrinoid necrosis of coronary arteries,Cushing's syndrome, excessive CYP11B1 level, the ectopic ACTH syndrome,the change in adrenocortical mass, primary pigmented nodularadrenocortical disease (PPNAD) Carney complex (CNC), anorexia nervosa,chronic alcoholic poisoning, nicotine or cocaine withdrawal syndrome,the post-traumatic stress syndrome, the cognitive impairment after astroke, the cortisol-induced mineralocorticoid excess, comprisingadministering to the subject a therapeutically effective amount of acompound according to anyone of Formulae I-VIII, or a pharmaceuticallyacceptable salt thereof, such that the subject is treated.

In yet another embodiment, the invention pertains, at least in part, topharmaceutical compositions, comprising an effective amount of acompound according to anyone of Formulae I-VIII, or a pharmaceuticallyacceptable salt thereof, wherein said effective amount is effective totreat a disorder or disease mediated by aldosterone synthase and/orCYP11B1.

In still another embodiment, the invention pertains, at least in part,to combinations including pharmaceutical combinations of one or moretherapeutically active agents.

In another embodiment, the invention pertains, at least in part, to amethod for inhibiting aldosterone synthase and/or CYP11B1 in a subjectby administering to the subject a therapeutically effective amount of acompound according to anyone of Formulae I-VIII, or a pharmaceuticallyacceptable salt thereof such that aldosterone synthase and/or CYP11B1 isinhibited.

An alternative approach to ameliorate the deleterious effects ofaldosterone, provided by the present invention, is the suppression ofaldosterone production by aldosterone synthase inhibitors. Aldosteronesynthase is an enzyme responsible for the final steps of thebiosynthesis of aldosterone from deoxycorticosterone, via conversion ofcorticosterone to form 18-OH-corticosterone, which is then converted toaldosterone.

Accordingly, the invention pertains, at least in part, to compounds,pharmaceutical compositions containing the compound and methods of usethereof. The present invention also relates to novel compounds which maybe used, for example, as modulators and/or inhibitors of aldosteronesynthase and/or CYP11B1.

The compounds of the present invention may, for example, be used totreat various diseases or disorders hypokalemia, hypertension, Conn'sdisease, renal failure, in particular, chronic renal failure,restenosis, atherosclerosis, syndrome X, obesity, nephropathy,post-myocardial infarction, coronary heart diseases, increased formationof collagen, fibrosis and remodeling following hypertension andendothelial dysfunction, cardiovascular diseases, renal dysfunction,liver diseases, cerebrovascular diseases, vascular diseases,retinopathy, neuropathy, insulinopathy, edema, endothelial dysfunction,baroreceptor dysfunction, migraine headaches, heart failure such ascongestive heart failure, arrhythmia, diastolic dysfunction, leftventricular diastolic dysfunction, diastolic heart failure, impaireddiastolic filling, systolic dysfunction, ischemia, hypertrophiccardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis,impaired arterial compliance, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, decreasedejection fraction, cardiac lesions, vascular wall hypertrophy,endothelial thickening, fibrinoid necrosis of coronary arteries,Cushing's syndrome, excessive CYP11B1 level, the ectopic ACTH syndrome,the change in adrenocortical mass, primary pigmented nodularadrenocortical disease (PPNAD) Carney complex (CNC), anorexia nervosa,chronic alcoholic poisoning, nicotine or cocaine withdrawal syndrome,the post-traumatic stress syndrome, the cognitive impairment after astroke, the cortisol-induced mineralocorticoid excess.

DETAILED DESCRIPTION OF THE INVENTION Compounds of the Invention

References hereinafter to compounds of Formula I apply equally tocompounds of Formulae II-VIII.

References hereinafter to embodiments of the invention apply equally tocompounds of Formula I and compounds of Formulae II-VIII, insofar as theembodiments are present.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

In one embodiment the invention provides a compound of the Formula I

a pharmaceutically acceptable salt thereof, wherein:

X is CH₂, O, S or —NR¹;

each R¹ are independently C₁₋₇alkyl or C₃₋₈cycloalkyl;

each of R² and R⁶ are independently hydrogen, halogen, cyano, C₁₋₇alkyl,hydroxy-C₁₋₇alkyl, —OR⁷, C₃₋₈cycloalkyl, halo-C₁₋₇alkyl or—CH₂—NR⁸—SO₂—R¹⁰;

R³ and R⁴ are independently hydrogen, halogen or cyano;

R⁵ is hydrogen, C₁₋₇alkyl, halogen, cyano, hydroxy, hydroxy-C₁₋₇alkyl,hydroxy-C₃₋₈cycloalkylalkyl, C₁₋₇alkoxy-C₃₋₈alkyl, —OR⁷, C₆₋₁₀aryl,heteroaryl, heterocyclyl, C₃₋₈cycloalkyl, halo-C₁₋₇alkyl, —NR⁸R⁹,—CH₂NR⁸—C(O)NR⁸R⁹, —CH₂—NR⁸—SO₂—R¹⁰, —C(O)—R¹⁰, —SO₂R¹⁰, —C(O)—NR⁸R⁹,—SO₂—NR⁸R⁹, —NR⁸C(O)—R¹⁰, —CH₂CN or —NR⁸—SO₂—R¹⁰;

R⁷ is C₁₋₇alkyl, C₃₋₈cycloalkyl-C₁₋₇alkyl, heterocyclyl-C₁₋₇alkyl,C₆₋₁₀aryl-C₁₋₇alkyl, heteroaryl-C₁₋₇alkyl or —C(O)—R¹⁰; in whichC₆₋₁₀aryl, heteroaryl, C₁₋₇alkyl, heterocycyl and C₃₋₈cycloalkyl areoptionally substituted with C₁₋₇alkoxy, halo, halo-C₃₋₈alkoxy,C₁₋₇alkyl, OH or halo-C₁₋₇alkyl;

each of R⁸, R⁹ are independently hydrogen, C₁₋₇alkyl, halo-C₁₋₇alkyl,C₆₋₁₀aryl-C₁₋₇alkyl or heterocyclyl; or R⁸ and R⁹ can form together withthe nitrogen atom to which they are attached a 5- or 6-membered ringheterocyclyl, wherein said heterocyclyl optionally contain an additionalheteroatom selected from N, O or S and is optionally substituted withC₁₋₇alkyl; and

R¹⁰ is hydrogen, C₁₋₇alkyl, halo-C₁₋₇alkyl, C₆₋₁₀aryl-C₁₋₇alkyl, —NR⁸R⁹,or heterocycyl;

wherein each heteroaryl is a mono- or bicyclic aromatic moietycomprising 5-10 ring atoms selected from carbon atoms and 1 to 5heteroatoms, and

each heterocyclyl is a mono- or bicyclic saturated or partiallysaturated but non-aromatic moiety comprising 4-10 ring ring atomsselected from carbon atoms and 1 to 5 heteroatoms; and each heteroatomsbeing O, N or S; and with the proviso that when R⁵ is halogen orhydrogen than at least one of R² and R⁶ is other than H.

In one embodiment, the invention pertains to compounds of Formula I,

or a pharmaceutically acceptable salt thereof, wherein:

X is CH₂, O, S or —NR¹;

each R¹ are independently C₁₋₇alkyl or C₃₋₈cycloalkyl;

each of R² and R⁶ are independently hydrogen, halogen, cyano, C₁₋₇alkyl,hydroxy-C₁₋₇alkyl, —OR⁷, C₃₋₈cycloalkyl, halo-C₁₋₇alkyl or—CH₂—NR⁸—SO₂R¹⁰;

R³ and R⁴ are independently hydrogen, halogen or cyano;

R⁵ is hydrogen, C₁₋₇alkyl, halogen, cyano, hydroxy, hydroxy-C₁₋₇alkyl,hydroxy-C₃₋₈cycloalkylalkyl, C₁₋₇alkoxy-C₃₋₈alkyl, —OR⁷, C₆₋₁₀aryl,heteroaryl, heterocyclyl, C₃₋₈cycloalkyl, halo-C₁₋₇alkyl, —NR⁸R⁹,—CH—NR⁸—C(O)NR⁸R⁹, —CH₂NR⁸—SO₂R¹⁰, —C(O)—R¹⁰, —SOR¹⁰, —C(O)—NR⁸R⁹,—SO₂—NR⁸R⁹, —NR⁸C(O)—R¹⁰, —CH₂C or —NR⁸—SO₂R¹⁰;

R⁷ is C₁₋₇alkyl, C₃₋₈cycloalkyl-C₁₋₇alkyl, heterocyclyl-C₁₋₇alkyl,C₆₋₁₀aryl-C₁₋₇alkyl, heteroaryl-C₁₋₇alkyl or —C(O)—R¹⁰; in whichC₆₋₁₀aryl, heteroaryl, C₁₋₇alkyl, heterocyclyl and C₃₋₈cycloalkyl areoptionally substituted with C₁₋₇alkoxy, halo, halo-C₃₋₈alkoxy,C₁₋₇alkyl, OH or halo-C₁₋₇alkyl;

each of R⁸, R⁹ are independently hydrogen, C₁₋₇alkyl, halo-C₁₋₇alkyl,C₆₋₁₀aryl-C₁₋₇alkyl or heterocyclyl; or R⁸ and R⁹ can form together withthe nitrogen atom to which they are attached a 5- or 6-membered ringheterocyclyl, wherein said heterocyclyl optionally contain an additionalheteroatom selected from N, O or S and is optionally substituted withC₁₋₇alkyl; and

R¹⁰ i is hydrogen, C₁₋₇alkyl, halo-C₁₋₇alkyl, C₆₋₁₀aryl-C₁₋₇alkyl,—NR⁸R⁹, or heterocyclyl;

wherein each heteroaryl is a mono- or bicyclic aromatic moietycomprising 5-10 ring atoms selected from carbon atoms and 1 to 5heteroatoms, and

each heterocyclyl is a mono- or bicyclic saturated or partiallysaturated but non-aromatic moiety comprising 4-10 ring ring atomsselected from carbon atoms and 1 to 5 heteroatoms; and each heteroatomsbeing O, N or S; and with the proviso that when R⁵ is halogen orhydrogen than R² is other than H.

Certain compounds of Formula I include compounds of Formula II:

or a pharmaceutically acceptable salt thereof, wherein R³, R⁴, R⁵ and R⁶have the definitions of Formula I, supra.

Certain compounds of Formula I include compounds of Formula III:

or a pharmaceutically acceptable salt thereof, wherein R³, R⁴, R⁵ and R⁶have the definitions of Formula I, supra.

Certain compounds of Formula I include compounds of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein R³, R⁴, R⁵ and R⁶have the definitions of Formula I, supra.

Certain compounds of Formula I include compounds of Formula V:

or a pharmaceutically acceptable salt thereof, wherein

R² is hydrogen, halogen, —OR⁷, or C₁₋₇alkyl;

R⁵ is hydrogen, C₁₋₇alkyl, halogen, C₆₋₁₀aryl, C₃₋₈cycloalkyl,heteroaryl, hydroxy, hydroxy-C₁₋₇alkyl, C₁₋₇alkoxy, halo-C₁₋₇alkyl,benzyloxy, —SO₂NR⁸R⁹, —CH₂NR⁸—SO₂—R¹⁰ or —NR⁸R⁹;

R⁶ is hydrogen or C₁₋₇alkyl;

R⁷ is C₁₋₇alkyl, C₂₋₈cycloalkyl-C₁₋₇alkyl, heterocyclyl-C₁₋₇alkyl,C₆₋₁₀aryl-C₁₋₇alkyl, heteroaryl-C₁₋₇alkyl or —C(O)—R¹⁰; and

each of R⁸, R⁹ and R¹⁰ are independently C₁₋₇alkyl or hydrogen.

Certain compounds of Formula I include compounds of Formula VI

or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, R⁵and R⁶ have the definitions of Formula I, supra.

Certain compounds of Formula I include compounds of Formula VII

or a pharmaceutically acceptable salt thereof, wherein R², R³, R⁴, R⁵and R⁶ have the definitions of Formula I, supra.

Certain compounds of Formula I include compounds of Formula VIII

or a pharmaceutically acceptable salt thereof, wherein R², R⁴, R⁵ and R⁶have the definitions of Formula I, supra.

One embodiment include compounds according to any one of Formulae I, VI,VII and VIII or of any classes and subclasses described herein, or apharmaceutically acceptable salt thereof, in which R¹ is C₁₋₄ alkyl(e.g., methyl, ethyl, propyl, isopropyl and butyl). In a particularaspect of this embodiment R¹ is methyl. In yet another embodiment, R¹ isC₃₋₈cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl).

Another embodiment include compounds according to any one of Formulae I,V, VI, VII and VIII or of any classes and subclasses described herein,or a pharmaceutically acceptable salt thereof, in which R² is hydrogen,halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, C₁₋₇alkyl(e.g., methyl ethyl, propyl, isopropyl and butyl), C₃₋₈cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), or —OR⁷. In aparticular aspect of this embodiment, R² is hydrogen, halogen, —OR⁷ orC₁₋₄alkyl. In yet another particular aspect of this embodiment, R² ishydrogen, chloro, methyl, methoxy or —O-benzyl. In a further aspect ofthis embodiment, R² is hydrogen, chloro, methyl, methoxy or —O-benzyland R¹ is methyl.

In another embodiment, R⁷ is C₁₋₄alkyl or arylalkyl.

In yet another embodiment, R⁷ is methyl, ethyl, isopropyl,—C(O)-isopropyl, or R⁷ is one of the following:

Another embodiment include compounds according to any one of Formulae I,V, VI, VII and VIII or of any classes and subclasses described herein,or a pharmaceutically acceptable salt thereof, in which R² is selectedfrom halo. OR⁷ and cycloalkyl. In a further aspect of this embodiment,R² is halo (e.g. chloro), cycloalkyl (e.g. cyclopropyl), benzyloxy,C₁₋₄alkoxy (e.g. methoxy, ethoxy) or heteroaryl-CH₂O—. In yet a furtheraspect of this embodiment, R⁵ is halo or H.

In one embodiment, this invention pertains to compounds according toanyone of Formulae I, II, III, IV, VI, VII and VIII or of any classesand subclasses described herein, or a pharmaceutically acceptable saltthereof, in which R³ and/or R⁴ is hydrogen. In another embodiment, thisinvention pertains to compounds according to anyone of Formulae I, II,III, IV, V, VI, VII and VIII or of any classes and subclasses describedherein, or a pharmaceutically acceptable salt thereof, in which R³ andR⁴ are independently halogen (e.g., fluorine, chlorine, bromine, iodine)or cyano.

Another embodiment include compounds of Formula I (or any of the otherFormulae, any other classes and/or subclasses of this invention), or apharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₇alkyl,cyano, hydroxy, hydroxy-C₁₋₇alkyl, hydroxy-C₃₋₈cycloalkylalkyl,C₁₋₇alkoxy-C₃₋₈alkyl, —OR⁷, C₆₋₁₀aryl, heteroaryl, heterocyclyl,C₃₋₈cycloalkyl, halo-C₁₋₇alkyl, —NR⁸R⁹, —CH₂—NR⁸—C(O)NR⁸R⁹,—CH₂NR⁸—SO₂—R¹⁰, —C(O)—R¹⁰, —SO₂R¹⁰, —C(O)—NR⁸R⁹, —SO—NR⁸R⁹,—NR⁸C(O)—R¹⁰, —CH₂CN, and —NR⁸—SO₂—R¹⁰.

Another embodiment include compounds of Formula I (or any otherformulae, any other classes and/or subclasses of this invention) or apharmaceutically acceptable salt thereof, in which R⁵ is hydrogen,C₁₋₇alkyl (e.g., methyl, ethyl, or isopropyl), halogen (e.g., chlorine,fluorine, or bromine), C₆₋₁₀aryl (e.g. phenyl), heteroaryl (e.g.pyridine), C₃₋₈cycloalkyl (e.g. cyclopropyl), cyano, hydroxy,hydroxyC₁₋₇alkyl (e.g. —CH₂OH, —CH(OH)isopropyl, —CH(OH)CH₂CH₃,—CH(OH)CH₃), C₁₋₇alkoxy (e.g., methoxy, ethoxy), benzyloxy,C₁₋₇alkoxy-C₁₋₇alkyl or —NR⁸R⁹, where R⁸ and R⁹ are each ethyl or R⁸ isH and R⁹ is ethyl. In a further aspect of this embodiment, the inventionpertains to compounds of Formula I (or any other formulae, any otherclasses and/or subclasses of this invention) or a pharmaceuticallyacceptable salt thereof, in which R⁵ is C₁₋₇alkyl (e.g., methyl, ethyl,or isopropyl), C₆₋₁₀aryl (e.g. phenyl), heteroaryl (e.g. pyridine),C₃₋₈cycloalkyl (e.g. cyclopropyl), cyano, hydroxy, hydroxyC₁₋₇alkyl(e.g. —CH₂OH, —CH(OH)isopropyl, —CH(OH)CH₂CH₃, —CH(OH)CH₃), C₁₋₇alkoxy(e.g., methoxy, ethoxy), benzyloxy, C₁₋₇alkoxy-C₁₋₇alkyl or —NR⁸R⁹,where R⁸ and R⁹ are each ethyl or R⁸ is H and R⁹ is ethyl.

In yet another embodiment, the invention pertains to compounds accordingto anyone of Formulae I to VIII, or a pharmaceutically acceptable saltthereof, wherein R⁵ is C₁₋₇alkyl (e.g., methyl, ethyl, isopropyl, orpentyl); C₁₋₇alkyl substituted with hydroxy (i.e. hydroxyalkyl);C₁₋₇alkyl substituted with C₁₋₇alkoxy (i.e. alkoxyalkyl); C₁₋₇alkylsubstitued with halogen (i.e. haloalkyl) or C₁₋₇alkyl substituted withcyano (e.g. —CH₂CN). Representative examples of this embodiment arecompounds of Formula I (or any other formulae, any other classes and/orsubclasses of this invention), or a pharmaceutically acceptable saltthereof, in which R⁵ is:

In yet another embodiment, R⁵ is —CH₂—NR⁸—SO₂—R¹⁰ or —CH₂—NR⁸C(O)—NR⁸R⁹.Representative examples of this embodiment are compounds of Formula I(or any other formulae, any other classes and/or subclasses of thisinvention), or a pharmaceutically acceptable salt thereof, in which R⁵is:

In another embodiment, R⁵ is C₆₋₁₀aryl, heteroaryl or heterocyclyl.Representative examples of this embodiment include compounds of FormulaI (or any other formulae, any other classes and/or subclasses of thisinvention), or a pharmaceutically acceptable salt thereof, in which R⁵is:

In another embodiment, R⁵ is C₃₋₈cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl) or C₃₋₈cycloalklyl substitutedwith hydroxy(hydroxycycloalkyl). Representative example ofhydroxycycloalkyl is:

In another embodiment, R⁵ is —NR⁸R⁹, —C(O)—R¹⁰, —SO₂R¹⁰, —C(O)—NR⁸R⁹,—SO₂—NR⁸R⁹, —NR⁸C(O)—R¹⁰ or —NR⁸—SO₂—R¹⁰. Representative examples ofthis embodiment include compounds of Formula I (or any other formulae,any other classes and/or subclasses of this invention), or apharmaceutically acceptable salt thereof, in which R⁵ is:

In one embodiment, the invention pertains to compounds according toanyone of Formulae I to VIII, or a pharmaceutically acceptable saltthereof, wherein R⁶ is hydrogen, halogen (e.g., fluorine, chlorine,bromine, iodine), cyano, C₁₋₇alkyl (e.g., methyl ethyl, propyl,isopropyl and butyl) or C₁₋₇alkyl substituted withhydroxy(hydroxyalkyl); C₁₋₇alkyl substituted withC₁₋₇alkoxy(alkoxyalkyl); C₁₋₇alkyl substituted with halogen (haloalkyl),or —NR⁸SO₂—R¹⁰, for example:

In another embodiment, the invention pertains to compounds according toanyone of Formulae I to VIII, or a pharmaceutically acceptable saltthereof, wherein R⁶ is hydrogen, or C₁₋₇alkyl (e.g., methyl).

In still another embodiment, examples of R⁸ and R⁹ include hydrogen andC₁₋₇alkyl (e.g., ethyl), resulting in, for example, —NR⁸R⁹ including—NH₂, —N(ethyl)₂, —NH(ethyl).

In still another embodiment, R⁸ and R⁹ form together with the atoms towhich they are attached an optionally substituted heterocyclyl. In arepresentative example, R⁸ and R⁹ form a piperidine, N-methylpiperidineor morpholine.

In yet another embodiment, examples of R¹⁰ include heterocycyl (e.g.,morpholino), C₁₋₇alkyl (e.g., methyl, ethyl, or isopropyl),halo-C₁₋₇alkyl (e.g., CF₃), and optionally substituted amino (e.g.,—NH₂, —NHCH(CH₃)₂, —N(methyl)₂).

In yet another embodiment, examples of —SO₂—NR⁸R⁹ include—SO₂—N(methyl)₂, —SO₂—NH(ethyl), and —SO₂NH(CH₂-4-fluoro-phenyl).

In yet another embodiment, examples of —C(O)—NR⁸R⁹ include —C(O)—NH₂,—C(O)—NH(isopropyl), —C(O)—N(methyl)₂.

In yet another embodiment, examples of —NR⁸—SO₂R¹⁰ include—N(methyl)-SO₂-ethyl and —NH—SO₂-methyl.

In another embodiment, examples of —NR⁸C(O)—R¹⁰ include—NH—C(O)-isopropyl.

In another embodiment the R¹ to R¹⁰ groups are those defined by theR¹-R¹⁰ groups, respectively, in Examples 1 to 52 in the Examples sectionbelow.

In another embodiment individual compounds according to the inventionare those listed in Examples 1 to 52 in the Examples section below, or apharmaceutically acceptable salt thereof.

DEFINITION

For purposes of interpreting this specification, the followingdefinitions will apply unless specified otherwise and wheneverappropriate, terms used in the singular will also include the plural andvice versa.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched (or straight chain or linear) hydrocarbon moiety, comprising1 to 20 carbon atoms. Preferably the alkyl comprises 1 to 7 carbonatoms, and more preferably 1 to 4 carbon atoms. Representative examplesof alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl,n-heptyl. The term “C₁₋₇alkyl” refers to a hydrocarbon having one toseven carbon atoms. Moreover, the term alkenyl includes both“unsubstituted alkyls” and “substituted alkyls”.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, that is substituted by one or more halo groups as definedherein. Preferably the haloalkyl can be monohaloalkyl, dihaloalkyl orpolyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo,bromo, chloro or fluoro within the alkyl group. Dihaloalky andpolyhaloalkyl groups can have two or more of the same halo atoms or acombination of different halo groups within the alkyl. Preferably, thepolyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2halo groups. Representative examples of haloalkyl are fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refersto an alkyl having all hydrogen atoms replaced with halo atoms. The term“halo-C₁₋₇alkyl” refers to a hydrocarbon having one to seven carbonatoms and being substituted by one or more halo groups.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Preferably, alkoxy groups have about 1-7, more preferablyabout 1-4 carbons. The term alkoxy include substituted alkoxy. Examplesof substituted alkoxy groups include halogenated alkoxy groups. Examplesof halogen substituted alkoxy groups are fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.The term “C₁₋₇alkoxy” refers to C₁₋₇alkyl-O—, wherein C₁₋₇alkyl isdefined above. Moreover, the term alkoxy includes both “unsubstitutedalkoxy” and “substituted alkoxy”.

The term alkoxyalkyl refers to an alkyl group, as defined above, inwhich the alkyl group is substituted with alkoxy. The term also includessubstituted alkoxyalkyl moiety.

The term “alkenyl” refers to a branched or unbranched hydrocarbon havingat least one carbon-carbon double bond. The term “C₂₋₇alkenyl” refers toa hydrocarbon having two to seven carbon atoms and comprising at leastone carbon-carbon double bond. Representative examples of alkenyl arevinyl, prop-1-enyl, allyl, butenyl, isopropenyl or isobutenyl. Moreover,the term alkenyl includes both “unsubstituted alkenyls” and “substitutedalkenyls”.

The term “alkenyoxy” refer to alkenyl-O— wherein alkenyl has thedefinition above.

The term “alkynyl” refers to a branched or unbranched hydrocarbon havingat least one carbon-carbon triple bond. The term “C₂₋₇-alkynyl” refersto a hydrocarbon having two to seven carbon atoms and comprising atleast one carbon-carbon triple bond. Representative examples of alkynylare ethynyl, prop-1-ynyl(propargyl), butynyl, isopropynyl or isobutynyl.Moreover, the term alkynyl includes both “unsubstituted alkynyls” and“substituted alkynyls”.

As used herein, the term “cycloalkyl” refers to saturated or partiallyunsaturated but non-aromatic monocyclic, bicyclic or tricyclichydrocarbon groups of 3-12 carbon atoms, preferably 3-8, or 3-7 carbonatoms. For bicyclic, and tricyclic cycloalkyl system, all rings arenon-aromatic. Exemplary monocyclic hydrocarbon groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl. Exemplary bicyclic hydrocarbon groups include bornyl,decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl. Exemplary tricyclichydrocarbon groups include adamantyl. The term “C₃₋₈cycloakyl” refers toa cyclic hydrocarbon groups having 3 to 8 carbon atoms.

The term “cycloalkylalkyl” refers to an alkyl as defined abovesubstituted with a cycloakyl as defined above.

The alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl groups may beoptionally substituted with one or more substituents Representativeexamples of substitutents for alkyl, alkenyl, alkynyl, alkoxy andcycloalkyl moities are oxo, ═S, halogen, hydroxy, cyano, nitro, alkyl,alkenyl, akynyl, alkoxy, alkenyloxy, alkynyloxy, halogen, alkylcarbonyl,alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl,aminocarbonyl, alkenylaminocarbonyl, alkoxycarbonyl, alkylcarbonyl,dialkylaminocarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, alkylcarbonylamino, alkylcarbonylalkylamino,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, aminosulfonyl,alkylsulfonyl, arylsulfonyl, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfamoyl, sulfonamido,heterocycyl, or an aromatic or heteroaromatic moiety, wherein each ofthe aforementioned hyrdorcarbon groups may be optionally substitutedwith one or more halogen, hydroxy or C₁₋₇alkoxy groups.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-20 carbon atoms in the ring portion. Preferably, thearyl is a (C₆₋₁₀aryl). The term aryl also refers to a group in which anaromatic ring is fused to one or more cycloalkyl rings, where the pointof attachment is on the aromatic ring or on the fused cycloalkyl ring.Representative examples of aryl are phenyl, naphthyl, anthracyl,phenanthryl or tetrahydronaphthyl. The term “C₆₋₁₀ aryl” refers to anaromatic hydrocarbon groups having 6 to 10 carbon atoms in the ringportion. Moreover, the term aryl includes both “unsubstituted aryl” and“substituted aryl”.

The term “arylalkyl” is an alkyl substituted with aryl. Representativeexamples of arylalkyl are benzyl or Phenyl-CH₂CH₂—. The term alsoincludes substituted arylalkyl moiety.

The term “Heteroaryl” includes monocyclic or bicyclic heteroaryl,containing from 5-10 ring members selected from carbon atoms and 1 to 5heteroatoms, and each heteroatoms is selected from O, N or S. Forbicyclic heteroaryl system, the system is fully aromatic (i.e. all ringsare aromatic).

Typical monocyclic heteroaryl groups include thienyl, furyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl,isoxazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, tetrazolyl, pyrid-2-yl,pyrid-3-yl, or pyridyl-4-yl, pyridazin-3-yl, pyridazin-4-yl,pyrazin-3-yl, 2-pyrazin-2-yl, pyrazin-4-yl, pyrazin-5-yl, 2-, 4-, or5-pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl. The term “heteroaryl”also refers to a group in which a heteroaromatic ring is fused to one ormore aryl, cycloaliphatic, or heterocyclyl rings, where the radical orpoint of attachment is on the heteroaromatic ring or on the fused aryl,cycloaliphatic or heterocycyl rings. Representative examples of bicyclicheteroaryl are indolyl, isoindolyl, indazolyl, indolizinyl, purinyl,quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, quinazolinyl, quinaxalinyl, phenanthridinyl,phenathrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl,benzisoqinolinyl, thieno[2,3-b]furanyl, furo[3,2-b]-pyranyl,5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl,4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl,imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl,7-benzo[b]thienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,benzoxapinyl, benzoxazinyl, 1H-pyrrolo[1,2-b][2]benzazapinyl,benzofuryl, benzothiophenyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl,imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl,pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl,pyrazolo[3,4-d]pyridinyl, pyrazolo[3,4-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl,pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl,pyrimido[5,4-d]pyrimidinyl, pyrazino-[2,3-b]pyrazinyl, orpyrimido[4,5-d]pyrimidinyl.

The term “heteroarylakyl” refers to alkyl substituted with heteroaryl.The term also includes substituted heteroarylalkyl moiety.

The aromatic ring of an “aryl” or “heteroaryl” group can be substitutedat one or more ring positions with such substituents as described above,as for example, halogen, hydroxy, cyano, nitro, alkyl, alkenyl, akynyl,alkoxy, alkenyloxy, alkynyloxy, halogen, alkylcarbonyl,alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,dialkylaminocarbonyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl,aminocarbonyl, alkenylaminocarbonyl, alkoxycarbonyl, alkylcarbonyl,dialkylaminocarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, alkylcarbonylamino, alkylcarbonylalkylamino,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, aminosulfonyl,alkylsulfonyl, arylsulfonyl, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfamoyl, sulfonamido,heterocyclyl, or an aromatic or heteroaromatic moiety, wherein each ofthe afore-mentioned hyrdorcarbon groups may be optionally substitutedwith one or more halogen, hydroxy or C₁₋₇alkoxy groups.

As used herein, the term “heterocycyl” or “heterocyclo” refers to asaturated or unsaturated non-aromatic ring (partially unsaturated) orring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-,8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or15-membered tricyclic ring system and contains at least one heteroatomselected from O, S and N, where the N and S can also optionally beoxidized to various oxidation states. For bicyclic and tricyclicheterocyclyl ring system, a non-aromatic ring system is defined as beinga non-fully or partially unsaturated ring system. Therefore bicyclic andtricyclic heterocycyl ring systems includes heterocyclyl ring systemswherein one of the fused rings is aromatic but the other(s) is (are)non-aromatic. In one embodiment, heterocyclyl moiety represents asaturated monocyclic ring containing from 5-7 ring atoms and optionallycontaining a further heteroatom, selected from O, S or N. Theheterocyclic group can be attached at a heteroatom or a carbon atom. Theheterocycyl can include fused or bridged rings as well as spirocyclicrings. Examples of heterocycles include dihydrofuranyl, dioxolanyl,dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl,oxathiolanyl, dithiolane, oxathianyl, thiomorpholino, oxiranyl,aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanyl, oxathianyl,thiepanyl, azepanyl, dioxepanyl, and diazepanyl.

The term “heterocyclyl” includes heterocyclic groups as defined hereinsubstituted with 1, 2 or 3 substituents such as alkyl, hydroxy (orprotected hydroxy), halo, oxo (e.g., ═O), amino, alkylamino ordialkylamino, alkoxy, cycloalkyl, carboxyl, heterocyclooxy, whereinheterocyclooxy denotes a heterocyclic group bonded through an oxygenbridge, alkyl-O—C(O)—, mercapto, nitro, cyano, sulfamoyl or sulfonamide,aryl, alkyl-C(O)—O—, aryl-C(O)—O—, aryl-S—, aryloxy, alkyl-S—, formyl(e.g., HC(O)—), carbamoyl, aryl-alkyl-, and aryl substituted with alkyl,cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(O)—NH—, alkylamino,dialkylamino or halogen.

The term “heterocyclylalkyl” is an alkyl substituted with heterocydyl.The term include substituted heterocyclylalkyl moiety.

The term “acyl” includes compounds and moieties which contain the acylradical (CH₃CO—) or a carbonyl group. It includes substituted acylmoieties. The term “substituted acyl” includes acyl groups where one ormore of the hydrogen atoms are replaced by for example, alkyl groups,alkynyl groups, halogens, hydroxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfonyl, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocycyl, alkylaryl, or an aromatic orheteroaromatic moiety.

The term “acylamino” includes moieties wherein an acyl moiety is bondedto an amino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

The term “aroyl” includes compounds and moieties with an aryl orheteroaromatic moiety bound to a carbonyl group. Examples of aroylgroups include phenylcarboxy, naphthyl carboxy. The term also includessubstituted aroyl moieties. The term “substituted aroyl” includes aroylgroups where one or more of the hydrogen atoms are replaced by forexample, halogen, hydroxy, cyano, nitro, alkyl, alkenyl, akynyl, alkoxy,alkenyloxy, alkynyloxy, halogen, alkylcarbonyl, alkylcarbonyloxy,arylcarbonyl, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,carboxylate, alkylcarbonyl, alkylaminoacarbonyl, dialkylaminocarbonyl,arylalkyl, heteroarylalkyl, heterocyclylalkyl, aminocarbonyl,alkenylaminocarbonyl, alkoxycarbonyl, alkylcarbonyl,dialkylaminocarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, alkylcarbonylamino, alkylcarbonylalkylamino,aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, aminosulfonyl,alkylsulfonyl, arylsulfonyl, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfamoyl, sulfonamido,heterocyclyl, or an aromatic or heteroaromatic moiety, wherein each ofthe afore-mentioned hyrdorcarbon groups may be optionally substitutedwith one or more halogen, hydroxy or C₁₋₇alkoxy groups.

The terms “alkoxyalkyl,” include alkyl groups, as described above, inwhich the alkyl group is substituted with an alkoxy as defined above.The term includes substituted alkoxyalkyl moiety.

The term “hydroxyalkyl” refers to alkyl groups, as described above, inwhich the alkyl group is substituted with a hydroxy. The term includessubstituted hydroxyalkyl moiety.

The term “hydroxycycloalkyl” refers to a cycloalkyl, as described above,in which the cycloalkyl is substituted with hydroxy. The term includessubstituted hydroxycycloalkyl moiety.

The term “hydroxycycloalkylalkyl” refers to a cycloalkylalkyl, asdefined above, in which the cycloalkylakyl is substituted with hydroxy.The term includes substituted hydroxycycloalkylalkyl moiety.

The term “carbamoyl” includes H₂NC(O)—, alkyl-NHC(O)—, (alkyl)₂NC(O)—,aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aryl-alkyl-NHC(O)—, alkyl(aryl-alkyl)-NC(O)—.The term includes substituted carbamoyl moieties.

The term “sulfonyl” includes R—SO₂—, wherein R is hydrogen, alkyl, aryl,heteroaryl, aryl-alkyl, heteroaryl-alkyl, alkoxy, aryloxy, cycloalkyl,or heterocyclyl.

The term “sulfonamido” includes alkyl-S(O)₂—NH—, aryl-S(O)₂NH—,aryl-alkyl-S(O)₂NH—, heteroaryl-S(O)₂NH—, heteroaryl-alkyl-S(O)₂NH—,alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂N(alkyl)-, aryl-alkyl-S(O)₂—N(alkyl)-,heteroaryl-S(O)₂N(alkyl)-, heteroaryl-alkyl-S(O)₂N(alkyl)-. The termincludes substituted carbamoyl moieties

The term “sulfamoyl” includes H₂NS(O)₂, alkyl-NHS(O)₂, (alkyl)₂NS(O)₂—,aryl-NHS(O)₂, alkyl(aryl)-NS(O)₂—, (aryl)₂NS(O)₂—, heteroaryl-NHS(O)₂—,(aryl-alkyl)-NHS(O)₂—, (heteroaryl-alkyl)-NHS(O)₂—. The term includessubstituted sulfamoyl moieties.

The term “aryloxy” includes an —O-aryl, wherein aryl is defined herein.The term includes substituted aryloxy moieties.

The term “heteroaryloxy” includes an —O-heteroaryl moiety, whereinheteroaryl is defined herein. The term includes substitutedheteroaryloxy moieties.

The term heterocyclyloxy includes an —O-heterocyclyl, whereinheterocycyl is defined herein. The term includes substitutedheterocyclyloxy moieties.

The term “amine” or “amino” includes compounds where a nitrogen atom iscovalently bonded to at least one carbon or heteroatom. The term “amine”or “amino” also includes —NH₂ and also includes substituted moieties.The term includes “alkyl amino” which comprises groups and compoundswherein the nitrogen is bound to at least one additional alkyl group.The term includes “dialkyl amino” groups wherein the nitrogen atom isbound to at least two additional independently selected alkyl groups.The term includes “arylamino” and “diarylamino” groups wherein thenitrogen is bound to at least one or two independently selected arylgroups, respectively.

The term “amide,” “amido” or “aminocarbonyl” includes compounds ormoieties which contain a nitrogen atom which is bound to the carbon of acarbonyl or a thiocarbonyl group. The term includes “alkaminocarbonyl”or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl oralkynyl groups bound to an amino group bound to a carbonyl group. Itincludes arylaminocarbonyl and arylcarbonylamino groups which includearyl or heteroaryl moieties bound to an amino group which is bound tothe carbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarbonyl,” “alkenylaminocarbonyl,” “alkynylaminocarbonyl,”“arylaminocarbonyl,” “alkylcarbonylamino,” “alkenylcarbonylamino,”“alkynylcarbonylamino,” and “arylcarbonylamino” are included in term“amide.” The term “amide,” “amido” or “aminocarbonyl” also includessubstituted moieties.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom. Thecarbonyl can be further substituted with any moiety which allows thecompounds of the invention to perform its intended function. Forexample, carbonyl moieties may be substituted with alkyls, alkenyls,alkynyls, aryls, alkoxy, aminos, etc. Examples of moieties which containa carbonyl include aldehydes, ketones, carboxylic acids, amides, esters,anhydrides, etc.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.The term also includes substituted moieties.

The term “ether” includes compounds or moieties which contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom which is covalentlybonded to another alkyl group. The term also includes substitutedmoieties.

The term “ester” includes compounds and moieties which contain a carbonor a heteroatom bound to an oxygen atom which is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are asdefined above. The term also includes substituted moieties.

The term “thioether” includes compounds and moieties which contain asulfur atom bonded to two different carbon or hetero atoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynys. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom which is bonded to an alkyl group. Similarly, the term“aldkthioalkenyls” and alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group. The term also includessubstituted moieties.

The term “hydroxy” or “hydroxyl” includes groups with an —OH.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

The terms “polycyclyl” or “polycyclic radical” refer to two or morecyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls) in which two or more carbons are common to twoadjoining rings, e.g., the rings are “fused rings.” Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl,arylcarbonyl, arylalkyl carbonyl, alkenylcarbonyl, aminocarbonyl,alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, cyano,amido, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or anaromatic or heteroaromatic moiety.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

It will be noted that the structure of some of the compounds of thisinvention includes asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers and diastereomers) are included within the scope of thisinvention, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and bystereochemically controlled synthesis. Furthermore, the structures andother compounds and moieties discussed in this application also includeall tautomers thereof.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R—S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat may be defined, in terms of absolute stereochemistry, as (R)- or(S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto. Pharmaceuticallyacceptable acid addition salts can be formed with inorganic acids andorganic acids, e.g., acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts. Inorganicacids from which salts can be derived include, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like; particularly preferred are the ammonium,potassium, sodium, calcium and magnesium salts. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, specifically such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. The pharmaceuticallyacceptable salts of the present invention can be synthesized from aparent compound, a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, non-aqueous media like ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are preferred, where practicable.Lists of additional suitable salts can be found, e.g., in “Remington'sPharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton,Pa., (1985); and in “Handbook of Pharmaceutical Salts Properties,Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. For example, anyhydrogen represented by “H” in any of the formulae herein is intended torepresent all isotopic forms of hydrogen (e.g. ¹H, ²H or D, ³H); anycarbon represented by “C” in any of the formulae herein is intended torepresent all isotopic forms of carbon (e.g. ¹¹C, ¹³C, ¹⁴C); anynitrogen represented by “N” is intended to represent all isotopic formsof nitrogen (e.g. ¹⁴N, ¹⁵N). Other examples of isotopes that areincluded in the invention include isotopes of oxygen, sulfur,phosphorous, fluorine, iodine and chlorine, such as ¹⁸F ³¹P, ³²P, ³⁵S,³⁶Cl, ¹²⁵I. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H, ¹³C, and ¹⁴C are present. In one embodiment, theatoms in the formulae herein occur in their natural abundance. Inanother embodiment, one or more hydrogen atom may be enriched in ²H;or/and one or more carbon atom may be enriched in ¹¹C, ¹³C or ¹⁴C;or/and one or more nitrogen may be enriched in ¹⁴N. Such isotopicallylabelled compounds are useful in metabolic studies (with ¹⁴C), reactionkinetic studies (with, for example ²H or ³H), detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Further, enrichment with heavier isotopes, particularly deuterium (i.e.,²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound according to any one of the formulae I toVIII. The concentration of such a heavier isotope, specificallydeuterium, may be defined by the isotopic enrichment factor. The term“isotopic enrichment factor” as used herein means the ratio between theisotopic abundance and the natural abundance of a specified isotope. Ifa substituent in a compound of this invention is denoted deuterium, suchcompound has an isotopic enrichment factor for each designated deuteriumatom of at least 3500 (52.5% deuterium incorporation at each designateddeuterium atom), at least 4000 (60% deuterium incorporation), at least4500 (67.5% deuterium incorporation), at least 5000 (75% deuteriumincorporation), at least 5500 (82.5% deuterium incorporation), at least6000 (90% deuterium incorporation), at least 6333.3 (95% deuteriumincorporation), at least 6466.7 (97% deuterium incorporation), at least6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation). Isotopically-enriched compounds according to any one offormulae I to VIII can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the accompanying Examples and Preparations using anappropriate isotopically-enriched reagent in place of the non-enrichedreagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of formula I that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula I by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula I with the co-crystal former under crystallization conditionsand isolating co-crystals thereby formed. Suitable co-crystal formersinclude those described in WO 2004/078163. Hence the invention furtherprovides co-crystals comprising a compound of formula I.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329). Except insofar as any conventional carrier is incompatiblewith the active ingredient, its use in the therapeutic or pharmaceuticalcompositions is contemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by aldosterone synthase and/or CYP11B1, or (ii)associated with aldosterone synthase and/or CYP11B1 activity, or (iii)characterized by abnormal activity of aldosterone synthase and/orCYP11B1; or (2) reduce or inhibit the activity of aldosterone synthaseand/or CYP11B1; or (3) reduce or inhibit the expression of aldosteronesynthase and/or CYP11B1. In another non-limiting embodiment, the term “atherapeutically effective amount” refers to the amount of the compoundof the present invention that, when administered to a cell, or a tissue,or a non-cellular biological material, or a medium, is effective to atleast partially reducing or inhibiting the activity of aldosteronesynthase and/or CYP11B1; or at least partially reducing or inhibitingthe expression of aldosterone synthase and/or CYP11B1.

As used herein, the term “subject” refers to an animal. Preferably, theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In a preferred embodiment, the subjectis a human.

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disorder, ordisease, or a significant decrease in the baseline activity of abiological activity or process.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., slowing or arresting or reducing the development of thedisease or at least one of the clinical symptoms thereof). In anotherembodiment “treating” or “treatment” refers to alleviating orameliorating at least one physical parameter including those which maynot be discernible by the patient. In yet another embodiment, “treating”or “treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers topreventing or delaying the onset or development or progression of thedisease or disorder.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Compounds of the present invention are either obtained in the free form,as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention may also form internalsalts, e.g., zwitterionic molecules.

The present invention also provides pro-drugs of the compounds of thepresent invention that converts in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally, bioprecursorprodrugs are compounds, which are inactive or have low activity comparedto the corresponding active drug compound, that contain one or moreprotective groups and are converted to an active form by metabolism orsolvolysis. Both the active drug form and any released metabolicproducts should have acceptably low toxicity.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. Carrier prodrugs can, forexample, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g., stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof (a) hydroxyl groups with lipophilic carboxylic acids (e.g., acarboxylic acid having at least one lipophilic moiety), or (b)carboxylic acid groups with lipophilic alcohols (e.g., an alcohol havingat least one lipophilic moiety, for example aliphatic alcohols).

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acylderivatives of thiols and O-acyl derivatives of alcohols or phenols,wherein acyl has a meaning as defined herein. Preferred arepharmaceutically acceptable ester derivatives convertible by solvolysisunder physiological conditions to the parent carboxylic acid, e.g.,lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzylesters, mono- or di-substituted lower alkyl esters, such as theω-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, the α-(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxymethyl ester and the like conventionally used in theart. In addition, amines have been masked as arylcarbonyloxymethylsubstituted derivatives which are cleaved by esterases in vivo releasingthe free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).Moreover, drugs containing an acidic NH group, such as imidazole, imide,indole and the like, have been masked with N-acyloxymethyl groups(Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups havebeen masked as esters and ethers. EP 039,051 (Sloan and Little)discloses Mannich-base hydroxamic acid prodrugs, their preparation anduse.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization.

General Synthetic Aspects

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group”, unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such asJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press,London and New York 1973, in T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Third edition, Wiley, New York 1999.

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known per se. Forexample, salts of compounds of the present invention having acid groupsmay be formed, for example, by treating the compounds with metalcompounds, such as alkali metal salts of suitable organic carboxylicacids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkalimetal or alkaline earth metal compounds, such as the correspondinghydroxides, carbonates or hydrogen carbonates, such as sodium orpotassium hydroxide, carbonate or hydrogen carbonate, with correspondingcalcium compounds or with ammonia or a suitable organic amine,stoichiometric amounts or only a small excess of the salt-forming agentpreferably being used. Acid addition salts of compounds of the presentinvention are obtained in customary manner, e.g. by treating thecompounds with an acid or a suitable anion exchange reagent. Internalsalts of compounds of the present invention containing acid and basicsalt-forming groups, e.g. a free carboxy group and a free amino group,may be formed, e.g. by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g. with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallisation and/or chromatographicseparation, for example over silica gel or by e.g. medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallisation, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, and the like.

The following applies in general to all processes mentioned hereinbefore and hereinafter.

All the above-mentioned process steps can be carried out under reactionconditions that are known per se, including those mentionedspecifically, in the absence or, customarily, in the presence ofsolvents or diluents, including, for example, solvents or diluents thatare inert towards the reagents used and dissolve them, in the absence orpresence of catalysts, condensation or neutralizing agents, for exampleion exchangers, such as cation exchangers, e.g. in the H+ form,depending on the nature of the reaction and/or of the reactants atreduced, normal or elevated temperature, for example in a temperaturerange of from about −100° C. to about 190° C., including, for example,from approximately −80° C. to approximately 150° C., for example at from−80 to −60° C., at room temperature, at from −20 to 40° C. or at refluxtemperature, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described under “Additional process steps”.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol, ethanol or 1- or 2-propanol, nitriles, such asacetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, methycyclohexane, or mixtures of those solvents, for exampleaqueous solutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4^(th) Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21).

The compounds of the invention can be synthesized using the methodsdescribed in the following schemes, examples, and by using artrecognized techniques. All compounds described herein are included inthe invention as compounds. Compounds of the invention may besynthesized according to at least one of the methods described inschemes 1-6.

Scheme 1 describes the synthesis of compounds according to Formula I,II, III, IV or V, wherein the variables R¹ to R⁶ are as defined inFormula I, supra.

In step one isatins of type A, where X is equal to either bromine,iodine, or hydrogen, can undergo alkylation via treatment with anon-nucleophilic base, preferably potassium carbonate, in the presenceof an alkyl halide, for example, iodomethane, at elevated temperatures,preferably 60° C., to afford compounds of type B. Compounds of type Bcan undergo reduction to oxindoles of type C upon treatment withhydrazine hydrate at elevated temperatures, preferably 130° C. When X isequal to bromine or iodine, step 3 can be omitted. However, when X isequal to hydrogen Step 3 permits halogenation to provide compounds oftype D. Step three can be accomplished via treatment with aqueousbromine in the presence of potassium bromide at elevated temperatures,preferably at 70° C. Compounds of type D can undergo Suzuki-typepalladium-catalyzed coupling with pyridines, such as E, which aresubstituted at the three position with a boronic acid or ester (e.g. Lis OH or O-alkyl), to furnish compounds of type F

Scheme 2 illustrates an alternative approach to compounds of type F,wherein variables R¹ to R⁶ are as previously defined in Formula I,supra. In Step 1 bromides of type D prepared as described in Scheme 1,can undergo a Miyaura-type borylation to furnish boronates of type G.Compounds of type G can undergo Suzuki-type palladium-catalyzed couplingwith pyridines, such as H, which are substituted at the three positionwith a bromine or iodine, to provide compounds of type F.

Alternatively, oxindoles of type D, wherein variable R¹ to R⁴ are aspreviously defined in Formula I, supra, can be prepared from indoles oftype I. In Step 1 the indole nitrogen can undergo alkylation upontreatment with a strong base, preferably sodium hydride, followed byreaction with an alkyl halide, for example, iodomethane. The resultingindoles of type J can then undergo a two step sequence of brominationwith concomitant hydrolysis, followed by reduction, preferably employingzinc dust in acetic acid to furnish oxindoles of type D.

Scheme 4 illustrates an approach to ethers of type M, which arecompounds of Formula I, wherein R² is OR⁷ and wherein variables R¹ to R⁷are as previously defined in Formula I, supra. In step 1 oxindoles oftype D where R² is equal to benzyloxy, prepared as described in Scheme 3can undergo a Suzuki-type palladium-catalyzed coupling with pyridines,such as E, which are substituted at the three position with a boronicacid or ester (e.g. L is OH or O-alkyl), to furnish compounds of type K.Hydrogenolysis of K, preferably employing a catalytic amount ofpalladium on carbon under a hydrogen atmosphere, affords phenols of typeL In step 3, L can undergo Mitsunobo-type coupling with primary orsecondary alcohols to provide ethers of type M. Preferably, employing1.5 to 2 equivalent of the primary or secondary alcohol in the presenceof cyanomethylene-tri-n-butylphosphorane at elevated temperatures.

Scheme 5 illustrates the synthesis of compounds of Formula I (X═O, S,—NR¹) wherein variables R¹ to R⁶ are as defined in Formula I, supra.Benzoxazolone or benzoxathiazolone or benzoimidazolone of type O can beprepared by reaction of aminophenyl N(X═OH, SH, —NHR¹; Y=Br or H) withCDI (Carbodiimide) or (tri)phosgene to generate compound O which canthen be treated with iodoalkyl in the precense of base (e.g. K₂CO₃) tofurnish P. Bromination of P (Y═H) by N-bromosuccinimide or bromine togenerate intermediate Q, which can then undergo Suzuki-typepalladium-catalyzed coupling with optionally substituted pyridyl borinicacid or ester, such as R, to generate a compound of Formula I (X═O, S,—NR¹).

Scheme 6 described an alternative synthesis of compound of Formula I,(X═O, S, —NR¹), wherein variables R¹ to R⁶ are as defined in Formula I,supra. A compound of type S (benzoxazolone when X is O, benzothiazolonewhen X is S, benzoimidazolone when X is N) can be converted into thecorresponding boronic ester using4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) andPdCl₂(dppf) or into boronic acid using lithium-halogen exchange followedby boronation to generate intermediate T. Intermediate T undergoesSuzuki coupling reaction with optionally substituted 3-bromo-pyridyne Uto generate a compound of the invention.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known per se.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention and apharmaceutically acceptable carrier. The pharmaceutical composition canbe formulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,etc. In addition, the pharmaceutical compositions of the presentinvention can be made up in a solid form including capsules, tablets,pills, granules, powders or suppositories, or in a liquid form includingsolutions, suspensions or emulsions. The pharmaceutical compositions canbe subjected to conventional pharmaceutical operations such assterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers and buffers etc.

Typically, the pharmaceutical compositions are tablets and gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable forthe manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate: granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with carrier. Carriers includeabsorbable pharmacologically acceptable solvents to assist passagethrough the skin of the host. For example, transdermal devices are inthe form of a bandage comprising a backing member, a reservoircontaining the compound optionally with carriers, optionally a ratecontrolling barrier to deliver the compound of the skin of the host at acontrolled and predetermined rate over a prolonged period of time, andmeans to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They are conveniently delivered in theform of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds. Anhydrous pharmaceutical compositionsand dosage forms of the invention can be prepared using anhydrous or lowmoisture containing ingredients and low moisture or low humidityconditions. An anhydrous pharmaceutical composition may be prepared andstored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions are preferably packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The compounds of formula I in free form or in pharmaceuticallyacceptable salt form, exhibit valuable pharmacological properties, e.g.aldosterone synthase and/or CYP11B1 modulating properties, e.g. asindicated in in vitro and in vivo tests as provided in the next sectionsand are therefore indicated for therapy.

Compounds of the invention may be useful in the treatment of anindication selected from: hypokalemia, hypertension, Conn's disease,renal failure, in particular, chronic renal failure, restenosis,atherosclerosis, syndrome X, obesity, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction, cardiovascular diseases, renal dysfunction, liver diseases,cerebrovascular diseases, vascular diseases, retinopathy, neuropathy,insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction,migraine headaches, heart failure such as congestive heart failure,arrhythmia, diastolic dysfunction, left ventricular diastolicdysfunction, diastolic heart failure, impaired diastolic filling,systolic dysfunction, ischemia, hypertrophic cardiomyopathy, suddencardiac death, myocardial and vascular fibrosis, impaired arterialcompliance, myocardial necrotic lesions, vascular damage, myocardialinfarction, left ventricular hypertrophy, decreased ejection fraction,cardiac lesions, vascular wall hypertrophy, endothelial thickening, orfibrinoid necrosis of coronary arteries, Cushing's syndrome, excessiveCYP11B1 level, the ectopic ACTH syndrome, the change in adrenocorticalmass, primary pigmented nodular adrenocortical disease (PPNAD) Carneycomplex (CNC), anorexia nervosa, chronic alcoholic poisoning, nicotineor cocaine withdrawal syndrome, the post-traumatic stress syndrome, thecognitive impairment after a stroke, the cortisol-inducedmineralocorticoid excess. Thus, as a further embodiment, the presentinvention provides the use of a compound according to anyone of formulaeI-VIII, or a pharmaceutically acceptable salt thereof, in therapy. In afurther embodiment, the therapy is selected from a disease which isameliorated by inhibition of aldosterone synthase and/or CYP11B1. Inanother embodiment, the disease is selected from the afore-mentionedlist, suitably hypokalemia, hypertension, congestive heart failure,atrial fibrillation, renal failure, in particular, chronic renalfailure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy,post-myocardial infarction, coronary heart diseases, increased formationof collagen, fibrosis such as cardiac or myocardiac fibrosis andremodeling following hypertension and endothelial dysfunction, moresuitably congestive heart failure, cardiac or myocardial fibrosis, renalfailure, hypertension or ventricular arrhythmia.

In another embodiment, the invention provides a method of treating adisease which is ameliorated by inhibition of aldosterone synthaseand/or CYP11B1 comprising administration of a therapeutically acceptableamount of a compound according to any one of formulae I-VIII. In afurther embodiment, the disease is selected from the afore-mentionedlist, suitably hypokalemia, hypertension, congestive heart failure,atrial fibrillation, renal failure, in particular, chronic renalfailure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy,post-myocardial infarction, coronary heart diseases, increased formationof collagen, fibrosis such as cardiac or myocardiac fibrosis andremodeling following hypertension and endothelial dysfunction, moresuitably congestive heart failure, cardiac or myocardial fibrosis, renalfailure, hypertension or ventricular arrhythmia.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 0.01-500 mg of active ingredient(s) for asubject of about 50-70 kg, or about 0.01-250 mg or about 0.01-150 mg orabout 0.01-100 mg, or about 0.01-50 mg of active ingredients. Thetherapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro tests. Thecompounds of the present invention can be applied in vitro in the formof solutions, e.g., preferably aqueous solutions. The dosage in vitromay range between about 10⁻³ molar and 10⁻⁹ molar concentrations. Atherapeutically effective amount in vivo may range depending on theroute of administration, between about 0.0001-500 mg/kg, or betweenabout 0.0001-100 mg/kg, or between about 0.0003-10 mg/kg.

The activity of a compound according to the present invention can beassessed by the in vitro methods described below.

In particular, the aldosterone synthase inhibitory activities in vitrocan be determined by the following assay.

Human adrenocortical carcinoma NCI-H295R cell line was obtained fromAmerican Type Culture Collection (Manassas, Va.).Insulin/transferrin/selenium (ITS)-A supplement (100×), DMEM/F-12,antibiotic/antimycotic (100×), and fetal bovine serum (FBS) werepurchased from Invitrogen (Carlsbad, Calif.). Anti-mouse PVTscintillation proximity assay (SPA) beads and NBS 96-well plates wereobtained from GE Health Sciences (Piscataway, N.J.) and Corning (Acton,Mass.), respectively. Solid black 96-well flat bottom plates werepurchased from Costar (Corning, N.Y.). Aldosterone and angiotensin (AngII) were purchased from Sigma (St. Louis, Mo.).D-[1,2,6,7-³H(N)]aldosterone was acquired from PerkinElmer (Boston,Mass.). Nu-serum was a product of BD Biosciences (Franklin Lakes, N.J.).

For in vitro measurement of aldosterone activity, human adrenocorticalcarcinoma NCI-H295R cells are seeded in NBS 96-well plates at a densityof 25,000 cells/well in 100 μl of a growth medium containing DMEM/F12supplemented with 10% FCS, 2.5% Nu-serum, 1 μg ITS/ml, and 1×antibiotic/antimycotic. The medium is changed after culturing for 3 daysat 37° C. under an atmosphere of 5% CO₂/95% air. On the following day,cells are rinsed with 100 μl of phosphate-buffered saline (PBS) andincubated with 100 μl of treatment medium containing 1 μM Ang II and acompound at different concentrations in quadruplicate wells at 37° C.for 24 hr. At the end of incubation, 50 μl of medium is withdrawn fromeach well for measurement of aldosterone production by an SPA usingmouse anti-aldosterone monoclonal antibodies.

Measurement of aldosterone activity can also be performed using a96-well plate format. Each test sample is incubated with 0.02 μCi ofD-[1,2,6,7-³H(N)]aldosterone and 0.3 μg of anti-aldosterone antibody inPBS containing 0.1% Triton X-100, 0.1% bovine serum albumin, and 12%glycerol in a total volume of 200 μl at room temperature for 1 hr.Anti-mouse PVT SPA beads (50 μl) are then added to each well andincubated overnight at room temperature prior to counting in a Microbetaplate counter. The amount of aldosterone in each sample is calculated bycomparing with a standard curve generated using known quantities of thehormone.

The in vitro inhibitory activities for CYP11B1 can be determined by thefollowing assay.

The cell line NCI-H295R was originally isolated from an adrenocorticalcarcinoma and has been characterized in the literature through thestimulable secretion of steroid hormones and the presence of the enzymesessential for steroidogenesis. Thus, the NCI-H295R cells have Cyp11 B1(steroid 11 β-hydroxylase). The cells show the physiological property ofzonally undifferentiated human foetal adrenocortical cells which,however, have the capacity to produce the steroid hormones which areformed in the three, phenotypically distinguishable zones in the adultadrenal cortex.

The NCI-H295R cells (American Type Culture Collection, ATCC, Rockville,Md., USA) are grown in Dulbeoco's Modified Eagle′Ham F-12 Medium(DME/F12), which has been supplemented with Ulroser SF Serum (Soprachem,Cergy-Saint-Christophe, France), insulin, transferrin, selenite (I-T-S,Becton Dickinson Biosiences, Franklin lakes, NJ, USA) and antibiotics in75 cm² cell culture vessels at 37° C. and in a 95% air-5% carbon dioxideatmosphere. The cells are subsequently transferred for colony formationinto a 24-well incubation vessel. They are cultivated there in DME/F12medium, which is now supplemented with 0.1% bovine serum instead ofUltroser SF for 24 hours. The experiment is initiated by cultivating thecells in DME/F12 medium which is supplemented with 0.1% bovine serumalbumin and test compound, in the presence or absence of cellstimulants, for 72 hours. The test substance is added in a concentrationrange from 0.2 nanomolar to 20 millimolar. Cell stimulants which can beused are angiotensin II (1D or 100 nanomolar), potassium ions (16millimolar), forskolin (10 micromolar) or a combination of twostimulants.

The excretion of aldosterone, cortisol, corticosterone andestradiol/estrone into the culture medium can be detected and quantifiedby commercially available, specific monoclonal antibodies inradioimmunoassays in accordance with the manufacturer's instructions.

Inhibition of the release of certain steroids can be used as a measureof the respective enzyme inhibition by the added test compounds. Thedose-dependent inhibition of enzymic activity by a compound iscalculated by means of an inhibition plot which is characterized by anIC50.

The IC50 values for active test compounds are ascertained by a simplelinear regression analysis in order to construct inhibition plotswithout data weighting. The inhibition plot is calculated by fitting a4-parameter logistic function to the raw data points using the leastsquares method. The equation of the 4-parameter logistic function iscalculated as follows: Y=(d−a)/((1+(x/c)b))+a, where: a=minimum datalevel, b=gradient, I c=ICED, d=maximum data level, x=inhibitorconcentration.

The inhibition activity of aldosterone production can also be expressedin percentage inhibition (% inhibition) at a given concentration (e.g. %inhibition at 1 μM), which is the aldosterone level when the cell istreated with the given concentration of a compound of this invention(e.g. concentration of 1 μM) versus the aldosterone excretion when cellis free of the compound of the invention:

% inhibition aldosterone production=[(Y−X)/Y]×100

wherein X is the level of aldosterone when the cell is treated with acompound of Formula I; andY is the level of aldosterone when the cell is free of compound ofFormula I.

The inhibition activity of cortisol production (CYP11B1 activity) canalso be expressed in percentage inhibition (% inhibition) at a givenconcentration (e.g. % inhibition at 1 μM), which is the cortisol levelwhen cell is treated with the given concentration of a compound of theinvention (e.g. concentration of 1 μM) versus the cortisol excretionwhen cell is free of the compound of the invention:

% inhibition cortisol production=[(Y′−X′)/Y′]×100

wherein X′ is the level of cortisol when the cell is treated with acompound of Formula I; andY′ is the level of cortisol when the cell is free of compound of FormulaI.

Using the test assays (as described above) compounds of the inventionexhibit inhibitory efficacy as shown in Table 1, provided infra.

TABLE 1 Inhibitory Activity of Compounds Aldosterone Cortisol cell cellsecretion secretion (% Inhib. # Compound (IC50 nM) @ 1 μM) 11-Methyl-5-(4-trifluoromethyl- 91.5 29.5pyridin-3-yl)-1,3-dihydro-indol-2- one 24-(4-Chloro-benzyloxy)-1-methyl- 5 835-pyridin-3-yl-1,3-dihydro-indol-2- one 34-Benzyloxy-1-methyl-5-pyridin-3- 18 51 yl-1,3-dihydro-indol-2-one 44-Chloro-1-methyl-5-pyridin-3-yl- 10 85.5 1,3-dihydro-indol-2-one 54-Chloro-5-(5-diethylamino- 58 78 pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one 6 4-Chloro-5-(5-hydroxymethyl- 11 83pyridin-3-yl)-1-methyl-1,3-dihydro- indol-2-one 74-Cyclopropyl-1-methyl-5-pyridin- 27.5 50 3-yl-1,3-dihydro-indol-2-one 84-Methoxy-1-methyl-5-pyridin-3- 36 84 yl-1,3-dihydro-indol-2-one 95-(1-Methyl-2-oxo-2,3-dihydro- 15 89 1H-indol-5-yl)-pyridine-3-sulfonicacid dimethylamide 10 5-(5-Bromo-pyridin-3-yl)-1,4- 4 93dimethyl-1,3-dihydro-indol-2-one 11 5-(5-Chloro-4-methyl-pyridin-3-yl)-37 39 4-methoxy-1-methyl-1,3-dihydro- indol-2-one 125-(5-Cyclopropyl-pyridin-3-yl)-1- 2 79 methyl-1,3-dihydro-indol-2-one 135-(5-Ethoxy-pyridin-3-yl)-1- 20 83.5 methyl-1,3-dihydro-indol-2-one 145-[3,3′]Bipyridinyl-5-yl-1-methyl- 18 60 1,3-dihydro-indol-2-one 156-Chloro-1-methyl-5-pyridin-3-yl- 171.5 82 1,3-dihydro-indol-2-one 163-Methyl-6-pyridin-3-yl-3H- 14 87 benzothiazol-2-one 176-(5-aminopyridin-3-yl)-3- 102 41 methylbenzo[d]thiazol-2(3H)-one 181,3-Dimethyl-5-pyridin-3-yl-1,3- 408 — dihydro-benzoimidazol-2-one 193-Methyl-6-pyridin-3-yl-3H- 472 — benzooxazol-2-one

The compound of the present invention may be administered eithersimultaneously with, or before or after, at least one other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition.

In one embodiment, the invention provides a product comprising acompound according to anyone of formulae I-VIII, or a pharmaceuticallyacceptable salt thereof and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease orcondition mediated by aldosterone synthase and/or CYP11B1. Productsprovided as a combined preparation include a composition comprising thecompound of formula (I) and the other therapeutic agent(s) together inthe same pharmaceutical composition, or the compound of formula (I) andthe other therapeutic agent(s) in separate form, e.g. in the form of akit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound according to anyone of formulae I-VIII, or apharmaceutically acceptable salt thereof, and another therapeuticagent(s). Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound according to anyone of formulae I-VIII, or a pharmaceuticallyacceptable salt thereof. In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound according toanyone of formulae I-VIII, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for treating a disease orcondition mediated by aldosterone synthase and/or CYP11B1, wherein themedicament is prepared for administration with another therapeuticagent. The invention also provides the use of a another therapeuticagent in the manufacture of medicament for treating a disease orcondition mediated by aldosterone synthase and/or CYP11B1, wherein themedicament is prepared for administration with a compound according toanyone of formulae I-VIII, or a pharmaceutically acceptable saltthereof.

The invention also provides a compound according to anyone of formulaeI-VIII, or a pharmaceutically acceptable salt thereof, for use in amethod of treating a disease or condition mediated by aldosteronesynthase and/or CYP11B1, wherein the compound according to anyone offormulae I-VIII, or a pharmaceutically acceptable salt thereof, isprepared for administration with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition mediated by aldosterone synthase and/orCYP11B1, wherein the other therapeutic agent is prepared foradministration with a compound according to anyone of formulae I-VIII,or a pharmaceutically acceptable salt thereof. The invention alsoprovides a compound according to anyone of formulae I-VIII, or apharmaceutically acceptable salt thereof, for use in a method oftreating a disease or condition mediated by aldosterone synthase and/orCYP11B1, wherein the compound according to anyone of formulae I-VIII, ora pharmaceutically acceptable salt thereof, is administered with anothertherapeutic agent. The invention also provides another therapeutic agentfor use in a method of treating a disease or condition mediated byaldosterone synthase and/or CYP11B1, wherein the other therapeutic agentis administered with a compound according to anyone of formulae I-VIII,or a pharmaceutically acceptable salt thereof.

The invention also provides the use of a compound according to anyone offormulae I-VIII, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for treating a disease or condition mediatedby aldosterone synthase and/or CYP11B1, wherein the patient haspreviously (e.g. within 24 hours) been treated with another therapeuticagent. The invention also provides the use of another therapeutic agentin the manufacture of a medicament for treating a disease or conditionmediated by aldosterone synthase and/or CYP11B1, wherein the patient haspreviously (e.g. within 24 hours) been treated with a compound accordingto anyone of formulae I-VIII.

In one embodiment, the other therapeutic agent is selected from:HMG-Co-A reductase inhibitor, an angiotensin II receptor antagonist,angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker(CCB), a dual angiotensin converting enzyme/neutral endopeptidase(ACE/NEP) inhibitor, an endothelin antagonist, a renin inhibitor, adiuretic, an ApoA-I mimic, an anti-diabetic agent, an obesity-reducingagent, an aldosterone receptor blocker, an endothelin receptor blocker,or a CETP inhibitor.

In still another embodiment, the invention pertains, at least in part,to methods wherein the compound of the invention (e.g., a compoundaccording to anyone of Formulae I-VIII or a compound otherwise describedherein) is administered in combination with a second agent.

The term “in combination with” a second agent or treatment includesco-administration of the compound of the invention (e.g., a compoundaccording to anyone of Formulae I-VIII or a compound otherwise describedherein) with the second agent or treatment, administration of thecompound of the invention first, followed by the second agent ortreatment and administration of the second agent or treatment first,followed by the compound of the invention.

The term “second agent” includes any agent which is known in the art totreat, prevent, or reduce the symptoms of a disease or disorderdescribed herein, e.g., an aldosterone synthase associated disorder,such as, for example, hypokalemia, hypertension, Conn's disease, renalfailure, in particular, chronic renal failure, restenosis,atherosclerosis, syndrome X, obesity, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction, cardiovascular diseases, renal dysfunction, liver diseases,cerebrovascular diseases, vascular diseases, retinopathy, neuropathy,insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction,migraine headaches, heart failure such as congestive heart failure,arrhythmia, diastolic dysfunction, left ventricular diastolicdysfunction, diastolic heart failure, impaired diastolic filling,systolic dysfunction, ischemia, hypertrophic cardiomyopathy, suddencardiac death, myocardial and vascular fibrosis, impaired arterialcompliance, myocardial necrotic lesions, vascular damage, myocardialinfarction, left ventricular hypertrophy, decreased ejection fraction,cardiac lesions, vascular wall hypertrophy, endothelial thickening, andfibrinoid necrosis of coronary arteries. Furthermore, the second agentmay be any agent of benefit to the patient when administered incombination with the administration of a compound of the invention.

Examples of second agents include HMG-Co-A reductase inhibitors,angiotensin II receptor antagonists, angiotensin converting enzyme (ACE)Inhibitors, calcium channel blockers (CCB), dual angiotensin convertingenzyme/neutral endopeptidase (ACE/NEP) inhibitors, endothelinantagonists, renin inhibitors, diuretics, ApoA-I mimics, anti-diabeticagents, obesity-reducing agents, aldosterone receptor blockers,endothelin receptor blockers, and CETP inhibitors.

An angiotensin II receptor antagonist or a pharmaceutically acceptablesalt thereof is understood to be an active ingredient which bind to theAT₁-receptor subtype of angiotensin II receptor but do not result inactivation of the receptor. As a consequence of the inhibition of theAT₁ receptor, these antagonists can, for example, be employed asantihypertensives or for treating congestive heart failure.

The class of AT₁ receptor antagonists comprises compounds havingdiffering structural features, essentially preferred are thenon-peptidic ones. For example, mention may be made of the compoundswhich are selected from the group consisting of valsartan, losartan,candesartan, eprosartan, irbesartan, saprisartan, tasosartan,telmisartan, the compound with the designation E-1477 of the followingformula

the compound with the designation SC-52458 of the following formula

and the compound with the designation ZD-8731 of the following formula

or, in each case, a pharmaceutically acceptable salt thereof.

Preferred AT₁-receptor antagonist are those agents which have beenmarketed, most preferred is valsartan or a pharmaceutically acceptablesalt thereof.

The term “HMG-Co-A reductase inhibitor” (also calledbeta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors)includes active agents that may be used to lower the lipid levelsincluding cholesterol in blood. Examples include atorvastatin,cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin,fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin,rivastatin, simvastatin, and velostatin, or, pharmaceutically acceptablesalts thereof.

The term “ACE-inhibitor” (also called angiotensin converting enzymeinhibitors) includes molecules that interrupt the enzymatic degradationof angiotensin I to angiotensin II. Such compounds may be used for theregulation of blood pressure and for the treatment of congestive heartfailure. Examples include alacepril, benazepril, benazeprilat,captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat,fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril,ramipril, spirapril, temocapril, and trandolapril, or, pharmaceuticallyacceptables salt thereof.

The term “calcium channel blocker (CCB)” includes dihydropyridines(DHPs) and non-DHPs (e.g., diltiazem-type and verapamil-type CCBs).Examples include amlodipine, felodipine, ryosidine, isradipine,lacidipine, nicardipine, nifedipine, niguldipine, niludipine,nimodipine, nisoldipine, nitrendipine, and nivaldipine, and ispreferably a non-DHP representative selected from the group consistingof flunarizine, prenylamine, diltiazem, fendilne, gallopamil,mibefradil, anipamil, tiapamil and verapamil, or, pharmaceuticallyacceptable salts thereof. CCBs may be used as anti-hypertensive,anti-angina pectoris, or anti-arrhythmic drugs.

The term “dual angiotensin converting enzyme/neutral endopetidase(ACE/NEP) inhibitor” includes omapatrilate (cf. EP 629627), fasidotrilor fasidotrilate, or pharmaceutically acceptable salts thereof.

The term “endothelin antagonist” includes bosentan (cf. EP 526708 A),tezosentan (cf. WO 96/19459), or, pharmaceutically acceptable saltsthereof.

The term “renin inhibitor” includes ditekiren (chemical name:[1S-[1R*,2R*,4R*(1R*,2R*)]]-1-[(1,1-dimethylethoxy)carbonyl]-L-prolyI-L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alfa-methyl-L-histidinamide);terlakiren (chemical name:[R—(R*,S*)]-N-(4-morpholinylcarbonyl)-L-phenylalanyi-N-[1-(cyclohexylmethyl)-2-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-S-methyl-L-cysteineamide);Aliskiren (chemical name:(2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide)and zankiren (chemical name:[1S-[1R*[R*(R*)],2S*,3R*]]-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-alfa-[[2-[[(4-methyl-1-piperazinyl)sulfonyl]methyl]-1-oxo-3-phenylpropyl]-amino]-4-thiazolepropanamide),or, hydrochloride salts thereof, or, SPP630, SPP635 and SPP800 asdeveloped by Speedel, or RO 66-1132 and RO 66-1168 of Formula (A) and(B):

pharmaceutically acceptable salts thereof.The term “aliskiren”, if not defined specifically, is to be understoodboth as the free base and as a salt thereof, especially apharmaceutically acceptable salt thereof, most preferably ahemi-fumarate salt thereof.

The term “diuretic” includes thiazide derivatives (e.g., chlorothiazide,hydrochlorothiazide, methylclothiazide, and chlorothalidon).

The term “ApoA-1 mimic” includes D4F peptides (e.g., formulaD-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F)

The term “anti-diabetic agent” includes insulin secretion enhancers thatpromote the secretion of insulin from pancreatic β-cells. Examplesinclude biguanide derivatives (e.g., metformin), sulfonylureas (SU)(e.g. tolbutamide, chlorpropamide, tolazamide, acetohexamide,4-chloro-N-[(1-pyrrolidinylamino)carbonyl]-benzensulfonamide(glycopyramide), glibenclamide(glyburide), gliclazide,1-butyl-3-metanilylurea, carbutamide, glibonuride, glipizide,gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide,glymidine, glypinamide, phenbutamide, and tolylcyclamide), orpharmaceutically acceptable salts thereof. Further examples includephenylalanine derivatives (e.g.,nateglinide[N-(trans-4-isopropycyclohexylcarbonyl)-D-phenylalanine](cf.EP 196222 and EP 526171) of the formula

repaglinide[(S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl}benzoicacid](cf. EP 589874, EP 147850 A2, in particular Example 11 on page 61,and EP 207331 A1); calcium(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinlycarbonyl)-propionatedihydrate (e.g., mitiglinide (cf. EP 507534)); and glimepiride (cf. EP31058). Further examples include DPP-IV inhibitors, GLP-1 and GLP-1agonists.

DPP-IV is responsible for inactivating GLP-1. More particularly, DPP-IVgenerates a GLP-1 receptor antagonist and thereby shortens thephysiological response to GLP-1. GLP-1 is a major stimulator ofpancreatic insulin secretion and has direct beneficial effects onglucose disposal.

The DPP-IV inhibitor can be peptidic or, preferably, non-peptidic.DPP-IV inhibitors are in each case generically and specificallydisclosed e.g. in WO 98/19998, DE 196 16 486 A1, WO 00/34241 and WO95/15309, in each case in particular in the compound claims and thefinal products of the working examples, the subject-matter of the finalproducts, the pharmaceutical preparations and the claims are herebyincorporated into the present application by reference to thesepublications. Preferred are those compounds that are specificallydisclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241,respectively.

GLP-1 is an insulinotropic protein which is described, e.g., by W. E.Schmidt et al. in Diabetologia, 28, 1985, 704-707 and in U.S. Pat. No.5,705,483.

The term “GLP-1 agonists” includes variants and analogs ofGLP-1(7-36)NH₂ which are disclosed in particular in U.S. Pat. No.5,120,712, U.S. Pat. No. 5,118,666, U.S. Pat. No. 5,512,549, WO 91/11457and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826. Furtherexamples include GLP-1(7-37), in which compound the carboxy-terminalamide functionality of Arg³⁶ is displaced with Gly at the 37^(th)position of the GLP-1(7-36)NH₂ molecule and variants and analogs thereofincluding GLN⁹-GLP-1(7-37), D-GLN⁹-GLP-1(7-37), acetyl LYS⁹-GLP-1(7-37),LYS⁹-GLP-1(7-37) and, in particular, GLP-1(7-37)OH, VAL⁸-GLP-1(7-37),GLY⁸-GLP-1(7-37), THR⁸-GLP-1(7-37), MET⁸-GLP-1(7-37) and4-imidazopropionyl-GLP-1. Special preference is also given to the GLPagonist analog exendin-4, described by Greig et al. in Diabetologia1999, 42, 45-50.

Also included in the definition “anti-diabetic agent” are insulinsensitivity enhancers which restore impaired insulin receptor functionto reduce insulin resistance and consequently enhance the insulinsensitivity. Examples include hypoglycemic thiazolidinedione derivatives(e.g., glitazone,(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione(englitazone),5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione(darglitazone),5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione(ciglitazone),5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(DRF2189),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione(BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637),bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidine-2,4-dione(AD-5075),5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione(DN-108)5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methy}-thiazolidine-2,4-dione,5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione,5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione,5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(rosiglitazone),5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione(pioglitazone),5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}-thiazolidine-2,4-dione(troglitazone),5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]-thiazolidine-2,4-dione(MCC555),5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione(T-174) and5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide(KRP297)).

Further anti-diabetic agents include, insulin signaling pathwaymodulators, like inhibitors of protein tyrosine phosphatases (PTPases),antidiabetic non-small molecule mimetic compounds and inhibitors ofglutamine-fructose-6-phosphate amidotransferase (GFAT); compoundsinfluencing a dysregulated hepatic glucose production, like inhibitorsof glucose-6-phosphatase (G6Pase), inhibitors offructose-1,6-bisphosphatase (F-1,6-Bpase), inhibitors of glycogenphosphorylase (GP), glucagon receptor antagonists and inhibitors ofphosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenase kinase(PDHK) inhibitors; inhibitors of gastric emptying; insulin; inhibitorsof GSK-3; retinoid X receptor (RXR) agonists; agonists of Beta-3 AR;agonists of uncoupling proteins (UCPs); non-glitazone type PPARγagonists; dual PPARα/PPARγ agonists; antidiabetic vanadium containingcompounds; incretin hormones, like glucagon-like peptide-1 (GLP-1) andGLP-1 agonists; beta-cell imidazoline receptor antagonists; miglitol;α₂-adrenergic antagonists; and pharmaceutically acceptable saltsthereof.

The term “obesity-reducing agent” includes lipase inhibitors (e.g.,orlistat) and appetite suppressants (e.g., sibutramine and phentermine).

The term “aldosterone receptor blocker” includes spironolectone andeplerenone.

The term “endothelin receptor blocker” includes bosentan.

The term “CETP inhibitor” refers to a compound that inhibits thecholesteryl ester transfer protein (CETP) mediated transport of variouscholesteryl esters and triglycerides from HDL to LDL and VLDL. Such CETPinhibition activity is readily determined by those skilled in the artaccording to standard assays (e.g., U.S. Pat. No. 6,140,343). Examplesinclude compounds disclosed in U.S. Pat. No. 6,140,343 and U.S. Pat. No.6,197,786 (e.g.,[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (torcetrapib); compounds disclosed in U.S. Pat. No.6,723,752 (e.g.,(2R)-3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methy]-amino}-1,1,1-trifluoro-2-propanol);compounds disclosed in U.S. patent application Ser. No. 10/807,838;polypeptide derivatives disclosed in U.S. Pat. No. 5,512,548;rosenonolactone derivatives and phosphate-containing analogs ofcholesteryl ester disclosed in J. Antibiot., 49(8): 815-816 (1996), andBioorg. Med. Chem. Lett.; 6:1951-1954 (1996), respectively. Furthermore,the CETP inhibitors also include those disclosed in WO2000/017165,WO2005/095409 and WO2005/097806.

EXEMPLIFICATION OF THE INVENTION

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

Abbreviations: ATP: adenosine 5′-triphosphate AS: Aldosterone SynthaseBINAP: racemic 2,2′-bis(diphenylphosphino)- BOC: tertiary butyl carboxy1,1′-binaphthyl br: broad bs: broad singlet calcd: calculated CYP11B1:11-beta hydroxylase d: doublet DAST: (diethylamino)sulfur trifluoridedd: doublet of doublets DCM: dichloromethane DIEA: diethylisopropylamineDME: 1,4-dimethoxyethane DMF: N,N-dimethylformamide DMSO:dimethylsulfoxide DPPA: diphenylphosphorylazide DTT: dithiothreitolEDTA: ethylenediamine tetraacetic acid ESI: electrospray ionizationEtOAc: ethyl acetate h: hour(s) HATU:O-(7-azobenzotriazol-1-yl)-1,1,3,3- HOBt: 1-hydroxy-7-azabenzotriazoletetramethyluroniumhexafluorophosphate HPLC: high pressure liquidchromatography LCMS: liquid chromatography and mass spectrometry MeOD:methanol-d4 MeOH: methanol MS: mass spectrometry m: multiplet min:minutes m/z: mass to charge ratio n.d.: not determined NMR: nuclearmagnetic resonance ppm: parts per million Pr: propyl PyBOP:benzotriazol-1-yloxy rt: room temperatureTripyrrolidinophosphoniumhexafluorophosphate s: singlet t: triplet TFA:trifluoroacetic acid THF: tetrahydrofuran TLC: thin layer chromatographyTris•HCl: aminotris(hydroxymethyl) methane hydrochloride NBS:N-bromosuccinimide Dppf: diphenylphosphine AIBN: azobiisobutyronitrile

Example 1 1-Methyl-5-(5-methyl-pyridin-3-yl)-1,3-dihydro-indol-2-one

To 5-bromo-1-methyl-1,3-dihydro-indol-2-one (CAS#20870-90-0, 80 mg, 0.35mmol) was added 5-methyl-3-pyridinyl boronic acid (CAS#173999-18-3, 55mg, 0.39 mmol), in 1,2-dimethoxyethane (2.7 mL) and 2 M aqueous sodiumcarbonate (0.45 mL, 0.9 mmol). The reaction mixture was degassed andplaced under an argon atmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.09 mmol/gloading, (195 mg, 0.018 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 100° C. for 1.5 hours. Thereaction mixture was cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 6%) to afford1-methyl-5-(5-methyl-pyridin-3-yl)-1,3-dihydro-indol-2-one; HRMS: (ESI)m/z 239.1181 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.42 (s, 3H), 3.27(s, 3H), 3.61 (s, 2H), 6.93 (d, J=8.1 Hz, 1H), 7.45-7.58 (m, 2H), 7.67(s, 1H), 8.42 (s, 1H), 8.63 (s, 1H).

Example 2 5-(5-Fluoro-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To a solution of 5-fluoropyridine-3-boronic acid (CAS#872041-86-6, 80mg, 0.57 mmol) in 1,2-dimethoxyethane (0.7 mL) was added water (0.3 mL)and ethanol (0.2 mL). The solution was then charged with sodiumcarbonate (60 mg, 0.57 mmol), 5-bromo-1-methyl-1,3-dihydro-indol-2-one(CAS#20870-90-0, 132 mg, 0.57 mmol), anddichlorobis(triphenylphosphine)palladium (II) (CAS#13965-03-2, 20.3 mg,0.029 mmol). The reaction vessel was sealed and is heated by microwaveirradiation at 150° C. for 10 minutes. The reaction mixture was cooledto room temperature, filtered and concentrated. The resulting residuewas partially purified by semi-preparative reverse phase HPLC (20 to 90%acetonitrile/water w/0.1% TFA). Final purification was accomplished viasilica gel flash chromatography (methanol-dichloromethane, 0 to 7%) toafford 5-(5-fluoro-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; MS:(ES+) m/z 243 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.18 (s, 3H), 3.64(s, 2H), 7.13 (d, J=7.8 Hz, 1H), 7.73-7.77 (m, 2H), 8.03 (d, J=9.7 Hz,1H), 8.53 (d, J=2.7 Hz, 1H), 8.79 (s, 1H).

Example 3 a)1-Methyl-5-(4,4,6,6-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one

To a solution of 5-bromo-1-methyl-1,3-dihydro-indol-2-one(CAS#20870-90-0, 4.07 g, 18.00 mmol), in DMSO (50 mL) was addedbis(pinacolato)diboron (5.03 g, 19.80 mmol), and potassium acetate (5.30g, 54.0 mmol). Next,[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) complexedwith dichloromethane (CAS#72287-26-4, 0.417 g, 0.540 mmol) was added.The reaction mixture was degassed by bubbling nitrogen through thesolution for 3 minutes. The reaction was then heated at 80° C. for 18hr. The reaction was then poured into ice-water and extracted threetimes with diethyl ether. The organic extracts were combined, washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-heptane, 0 to 70%) to afford1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one;¹H NMR (400 MHz, CDCl₃) δ ppm 1.35 (s, 12H), 3.23 (s, 3H), 3.51 (s, 2H),6.83 (d, J=7.6 Hz, 1H), 7.69 (s, 1H), 7.77 (d, J=7.8 Hz, 1H).

b) 6-(6-Ethoxy-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one(137 mg, 0.5 mmol) was added 3-bromo-5-ethoxy-pyridine (CAS#17117-17-8,112 mg, 0.55 mmol), tripotassium phosphate (266 mg, 1.25 mmol) and DMF(2.5 mL). The reaction mixture was degassed and placed under an argonatmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.09 mmol/gloading, (300 mg, 0.027 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 100° C. for 75 minutes. Thereaction mixture was then cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 5%) to furnish5-(5-ethoxy-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI)m/z 269.1287 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.49 (t, J=6.9 Hz,3H), 3.27 (s, 3H), 3.62 (s, 2H), 4.18 (q, J=6.8 Hz, 2H), 6.93 (d, J=8.1Hz, 1H), 7.43 (s, 1H), 7.46-7.57 (m, 2H), 8.26 (d, J=2.5 Hz, 1H), 8.43(d, J=1.5 Hz, 1H).

Example 41-Methyl-5-[5-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-3-yl]-1,3-dihydro-indol-2-one

To1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one(109 mg, 0.4 mmol), prepared as described in Example 3a, was added3-bromo-5-(2-methyl-1,3-dioxolan-2-yl)pyridine (CAS#59936-01-5, 107 mg,0.44 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodiumcarbonate (0.45 mL, 0.9 mmol). The reaction mixture was degassed andplaced under an argon atmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (182 mg, 0.02 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 105° C. for 3 hours. Thereaction mixture was cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous-layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 6%) to afford1-methyl-5-[5-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-3-yl]-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 311.1395 (M+H)+; ¹H NMR (400 MHz, CDCl₃) δppm 1.73 (s,3H), 3.28 (s, 3H), 3.62 (s, 2H), 3.82-3.88 (m, 2H), 4.08-4.16 (m, 2H),6.94 (d, J=7.8 Hz, 1H), 7.49-7.58 (m, 2H), 7.97 (s, 1H), 8.71 (d, J=2.0Hz, 1H), 8.77 (d, J=2.3 Hz, 1H).

Example 5 5-(1-Methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-nicotinamide

To a solution of1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one,prepared as described in Example 3a (75 mg, 0.26 mmol) in1,2-dimethoxyethane (0.7 mL) was added water (0.3 mL) and ethanol (0.2mL). The solution was then charged with sodium carbonate (27.6 mg, 0.26mmol) and 5-bromonicotinamide (CAS#28733-43-9, 53.5 mg, 0.26 mmol) anddichlorobis(triphenylphosphine)palladium (II) (CAS#13965-03-2, 9.1 mg,0.013 mmol). The reaction vessel was sealed and was heated by microwaveirradiation at 150° C. for 10 minutes. The reaction mixture was cooledto room temperature, filtered and concentrated. The resulting residuewas purified by silica gel flash chromatography(methanol-dichloromethane, 0 to 10%) to furnish5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-nicotinamide; MS: (ES+) m/z268 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.16 (s, 3H), 3.63 (s, 2H),7.11 (d, J=8.8 Hz, 1H), 7.62 (br. s., 1H), 7.69-7.75 (m, 2H), 8.22 (br.s., 1H), 8.42 (t, J=2.0 Hz, 1H), 8.94 (dd, J=18.9, 1.96 Hz, 2H).

Example 6 a) 3-Bromo-4-vinyl-pyridine

To a solution of methyltriphenylphosphonium bromide (2.14 g, 6.00 mmol)in THF (27 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes,1.8 mL, 4.5 mmol). The resulting yellow reaction mixture was stirred for30 min at −78° C. In a separate flask THF (6 mL) was added to3-bromoisonicotinaldehyde (CAS#113118-81-3, 558 mg. 3.00 mmol). Theresulting 3-bromoisonicotinaldehyde solution was the transferred, viacannula, to the phosphonium ylide mixture followed by a 2 mL THF wash.The reaction was allowed to warm to room temperature over 60 minutes andthen permitted to stir for an additional 30 minutes. The reaction wasthen quenched with saturated aqueous sodium bicarbonate and diluted withethyl acetate. The layers were separated and the organic layer waswashed with saturated aqueous sodium bicarbonate. The organic layer wasconcentrated to near dryness. The resulting residue was then dilutedwith ethyl acetate and 1M sodium bisulfate and the layers wereseparated. The organic layer was extracted two additional times with 1Msodium bisulfate. The aqueous layers were combined, diluted withdichloromethane, and neutralized via the careful addition of saturatedaqueous sodium bicarbonate and solid sodium carbonate. The layers wereseparated and the now basic aqueous layer was extracted three additionaltimes with dichloromethane. The dichloromethane layers were combined,dried over anhydrous sodium sulfate, filtered and concentrated. Theresulting residue was purified by silica gel flash chromatography (ethylacetate-dichloromethane, 0 to 16%) to furnish 3-bromo-4-vinyl-pyridine;MS: (ES+) m/z 183.9 (M+H)⁺

b) 1-Methyl-5-(4-vinyl-pyridin-3-yl)-1,3-dihydro-indol-2-one

To1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one(135 mg, 0.49 mmol), prepared as described in Example 3a, was added3-bromo-4-vinyl-pyridine (100 mg, 0.54 mmol), 1,2-dimethoxyethane (3.0mL), and 2 M aqueous sodium carbonate (0.560 mL, 1.1 mmol). The reactionmixture was degassed and placed under an argon atmosphere, at which timeresin bound tetrakis(triphenylphosphine)palladium(0), specificallypolystyrene triphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage),0.11 mmol/g loading, (225 mg, 0.025 mmol)] was added. The reactionvessel was sealed and was heated by microwave irradiation at 115° C. for4 hours. The reaction mixture was cooled to room temperature, dilutedwith dichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 6%) to furnish1-methyl-5-(4-vinyl-pyridin-3-yl)-1,3-dihydro-indol-2-one; MS: (ES+) m/z251.3 (M+H)⁺.

c) 6-(4-Ethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To a solution of1-methyl-5-(4-vinyl-pyridin-3-yl)-1,3-dihydro-indol-2-one (30 mg, 0.12mmol) in ethanol (1 mL) was added 10% palladium on carbon (18 mg, 0.02mmol). The atmosphere over the reaction mixture was evacuated and thereaction was placed under an atmosphere of hydrogen gas via a balloon.The reaction was stirred for 25 minutes. The reaction mixture was thenfiltered through a plug of Celite® and the filtrate was thenconcentrated to dryness. The resulting residue was purified by silicagel flash chromatography (ethanol-dichloromethane, 0 to 6%) to afford5-(4-ethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one. The HCl saltof the title compound was prepared by dissolution in diethyl etherfollowed by treatment with an excess of 1N HCl in diethyl ether. Theresulting heterogeneous solution was concentrated to furnish the HClsalt of 5-(4-ethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one. HRMS:(ESI) m/z 253.1335 (M+H)+; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.23 (t, J=7.6Hz, 3H), 2.93 (q, J=7.6 Hz, 2H), 3.28 (s, 3H), 3.66 (s, 2H) 7.16 (d,J=8.6 Hz, 1H), 7.33-7.43 (m, 2H), 8.05 (d, J=6.3 Hz, 1H), 8.65 (s, 1H),8.71 (d, J=6.1 Hz, 1H).

Example 7 a) 5-Bromo-pyridine-3-sulfonic acid 4-fluoro-benzylamide

To a solution of 5-bromo-3-pyridinesulfonyl chloride (CAS#65001-21-0,256 mg, 1.0 mmol) in dichloromethane (8 mL) at 0° C. was addeddiisopropylethylamine (0.350 mL, 2.0 mmol) followed by4-fluorobenzylamine (CAS#140-75-0, 0.11 mL, 0.95 mmol). The reaction wasput at room temperature and stirred for 15 minutes. The reaction wasthen poured into water and diluted with dichloromethane. The layers wereseparated and the aqueous layer was extracted two additional times withdichloromethane. The organic layers were combined, dried over anhydroussodium sulfate, filtered, and concentrated to furnish5-bromo-pyridine-3-sulfonic acid 4-fluoro-benzylamide without the needfor further purification. MS: (ES+) m/z 344.8 (M+H)⁺

b) 5-(1-Methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridine-3-sulfonic acid4-fluoro-benzylamide

To1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one,prepared as described in Example 3a (124 mg, 0.45 mmol) was addedbromo-pyridine-3-sulfonic acid 4-fluoro-benzylamide (140 mg, 0.41 mmol),tripotassium phosphate (260 mg, 1.25 mmol) and DMF (2.5 mL). Thereaction mixture was degassed and placed under an argon atmosphere, atwhich time tetrakis(triphenylphosphine)palladium(0), (23 mg, 0.02 mmol)]was added. The reaction vessel was sealed and was heated by microwaveirradiation at 100° C. for 60 minutes. The reaction mixture was thencooled to room temperature, diluted with dichloromethane and filteredthrough glass wool. The filtrate was further diluted with saturatedaqueous sodium bicarbonate and the layers were separated. The aqueouslayer was extracted two times with dichloromethane, and the organiclayers were combined, dried over anhydrous sodium sulfate, filtered, andconcentrated. The resulting residue was purified by silica gel flashchromatography (heptane-ethyl acetate, 20 to 100%) to furnish5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridine-3-sulfonic acid4-fluoro-benzylamide; HRMS: (ESI) m/z 412.1136 (M+H)⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.17 (s, 3H), 3.65 (s, 2H), 4.12 (s, 2H), 7.03 (t, J—=8.8Hz, 2H), 7.14 (d, J=8.1 Hz, 1H), 7.25 (dd, J=8.6, 5.6 Hz, 2H), 7.65 (s,1H), 7.67 (d, J=8.1 Hz, 1H), 8.20 (t, J=2.3 Hz, 1H), 8.44 (t, J=6.3 Hz,1H), 8.80 (d, J=2.0 Hz, 1H), 9.04 (d, J=2.3 Hz, 1H).

Example 8N-[5-(1-Methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridin-3-yl]-methanesulfonamide

To a solution of5-(5-amino-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one, prepared asdescribed in Example 3, (35 mg, 0.146 mmol), in dichloromethane (2.0 mL)was added diisopropylethylamine (75 μL, 0.44 mmol). The reaction wascooled to −10° C. and methanesulfonyl chloride (22 μL, 0.28 mmol) wasadded. After 15 minutes the reaction was quenched with saturated aqueoussodium bicarbonate and diluted with dichloromethane. The layers wereseparated and the organic layer was dried over sodium sulfate, filteredand concentrated. The resulting residue was dissolved in methanol (5 mL)and treated with 2 M aqueous sodium hydroxide (0.5 mL, 1 mmol) andpermitted to stir at room temperature for 10 minutes. The reaction wasthen diluted with dichloromethane and water and the pH of the solutionwas brought to ca. 7 via the careful addition of 1M aqueous HCl. Thelayers were separated and the aqueous layer was extracted fouradditional times with dichloromethane and one time with ethyl acetate.The organic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The resulting residue was purified by silicagel flash chromatography (ethanol-dichloromethane, 0 to 7%) to furnishN-[5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridin-3-yl]-methanesulfonamide;HRMS: (ES+) m/z 318.0912 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.11 (s,3H), 3.28 (s, 3H), 3.62 (s, 2H), 6.94 (d, J=8.1 Hz, 1H), 7.50 (s, 1H),7.51-7.59 (m, 1H), 7.91 (s, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.67 (d, J=1.8Hz, 1H).

Example 9N-[5-(1-Methyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-pyridin-3-yl]-isobutyramide

To a solution of5-(5-amino-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one, prepared asdescribed in Example 3, (30 mg, 0.125 mmol), in dichloromethane (6.0 mL)was added diisopropylethylamine (55 μL, 0.313 mmol). The reaction wascooled to 0° C. and isobutyryl chloride (20 μL, 0.19 mmol) was added.The reaction was placed at room temperature, and then after 10 minutes,the reaction was poured in to water and diluted with dichloromethane.The layers were separated and the aqueous layer was extracted twoadditional times with dichloromethane. The organic layers were combined,dried over anhydrous sodium sulfate, filtered, and concentrated. Theresulting residue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 7%) to provide;N-[5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridin-3-yl]-isobutyramide.HRMS: (ES+) m/z 310.1563 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13(d, J=6.8 Hz, 6H), 2.59-2.67 (m, 1H), 3.15 (s, 3H), 3.63 (s, 2H), 7.10(d, J=8.1 Hz, 1H), 7.55-7.58 (m, 2H), 7.59 (s, 1H), 8.33 (t, J=2.2 Hz,1H), 8.51 (d, J=2.0 Hz, 1H), 8.65 (d, J=2.3 Hz, 1H), 10.09 (s, 1H).

Example 10 a) (5-Bromo-pyridin-3-yl)-ethyl-amine and(5-Bromo-pyridin-3-yl)-diethyl-amine

To a solution of 3-amino-5-bromopyridine (CAS#13535-01-8, 520 mg, 3.0mmol) in THF (12 mL) at −78° C. was added potassiumbis(trimethylsilyl)amide (0.5 M in toluene, 6.9 mL, 3.45 mmol). Thereaction was stirred for 20 minutes at −78° C. and was then charged withiodoethane (0.25 mL, 3.15 mmol). The reaction was stirred for anadditional 30 minutes, at which time mixture was charged with additionalpotassium bis(trimethylsilyl)amide (0.5 M in toluene, 6.9 mL, 3.45 mmol)and iodoethane (0.25 mL, 3.15 mmol). The reaction was then permitted towarm to −20° C. over 2 h at which time it was quenched with aqueousammonium hydroxide (5 mL) and was stirred for 30 minutes at roomtemperature. The reaction was then diluted with brine and ethyl acetate.The layers were separated and the aqueous layer was extracted twoadditional times. The organic layers were combined, dried over anhydroussodium sulfate, filtered, and concentrated. The resulting residue waspurified by silica gel flash chromatography (ethyl acetate-heptane, 0 to60%) to afford both (5-bromo-pyridin-3-yl)-ethyl-amine and(5-bromo-pyridin-3-yl)-diethyl-amine separately.

(5-bromo-pyridin-3-yl)-ethyl-amine: MS: (ES+) m/z 200.9 (M+H)⁺(5-bromo-pyridin-3-yl)-diethyl-amine: MS: (ES+) m/z 229.0 (M+H)⁺

b) 5-(5-Diethylamino-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ES+) m/z 296.1769 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.12 (t, J=6.9 Hz, 6H), 3.15 (s, 3H), 3.42 (q, J=6.9 Hz, 4H), 3.61(s, 2H), 7.06 (d, J=8.6 Hz, 1H), 7.10 (t, 1H), 7.56-7.61 (m, 2H), 8.00(d, J=2.8 Hz, 1H), 8.03 (d, J=1.8 Hz, 1H).

c) 5-(5-Ethylamino-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ES+) m/z 268.1451 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.19 (t, J=7.1 Hz, 3H), 3.12 (q, 2H), 3.15 (s, 3H), 3.61 (s, 2H),5.85 (t, J=5.4 Hz, 1H), 7.03 (t, J=2.3 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H),7.53-7.58 (m, 2H), 7.90 (d, J=2.5 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H).

Example 11 a) Ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide

To a solution of 5-bromo-3-pyridinecarboxaldehyde (CAS#113118-81-3, 450mg, 2.4 mmol) in dichloroethane (15 mL) was added ethanesulfonamide(CAS#1520-70-3, 175 mg, 1.6 mmol), acetic acid (0.18 mL, 3.2 mmol),triethylamine (0.45 mL, 3.2 mmol) and sodium triacetoxyborohydride (1.0g, 4.8 mmol). The reaction was stirred at room temperature for 3 hours,at which time it was diluted with dichloromethane and saturated aqueoussodium bicarbonate. The layers were separated and the aqueous layer wasextracted two additional times with dichloromethane. The organic layerswere combined, dried over anhydrous sodium sulfate, filtered, andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-heptane, 10 to 100%) to provideethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide; MS: (ES+) m/z278.9 (M+H)⁺.

b) Ethanesulfonic acid[5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridin-3-ylmethyl]-amide

The above compound was prepared in a similar fashion as described inExample 3; HRMS: (ESI) m/z 346.1225 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃ δ ppm1.41 (t, J=7.3 Hz, 3H), 3.08 (q, J=7.5 Hz, 2H), 3.27 (s, 3H), 3.62 (s,2H), 4.43 (d, J=6.3 Hz, 2H), 4.74 (br. s., 1H), 6.94 (d, J=8.1 Hz, 1H),7.50 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.95 (br. s., 1H), 8.55 (br. s.,1H), 8.78 (br. s., 1H).

Example 12 a) Ethanesulfonic acid(5-bromo-pyridin-3-ylmethyl)-methyl-amide

To a solution of ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide(0.21 g, 0.752 mmol), prepared as described in Example 11a, in DMF (6mL) at −10° C., was added sodium hydride (60% oil dispersion, 39 mg,0.98 mmol). The reaction was stirred for 15 minutes at which timeiodomethane (0.056 ml, 0.903 mmol) dissolved in DMF (1 mL) was added.The reaction was stirred at −10° C. for an additional 15 minutes and wasthen quenched with ammonia hydroxide (2 mL). The reaction was dilutedwith brine and extracted three times with ethyl acetate. The organiclayers were combined, dried over anhydrous sodium sulfate, filtered, andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate, 0 to 80%) to provide ethanesulfonic acid(5-bromo-pyridin-3-ylmethyl)-methyl-amide; MS: (ES+) m/z 293.1 (M+H)⁺.

b) Ethanesulfonic acidmethyl-[5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridin-3-ylmethyl]-amide

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ESI) m/z 360.1387 (M+H)⁺; ¹H NMR (400 MHz, CD₂Cl₂ δppm 1.39 (t, J=7.5 Hz, 3H), 2.82 (s, 3H), 3.08 (q, J=7.3 Hz, 2H), 3.22(s, 3H), 3.57 (s, 2H), 4.43 (s, 2H), 6.94 (d, J=8.1 Hz, 1H), 7.52 (d,J=1.3 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.94 (s, 1H), 8.49 (d, J=2.0 Hz,1H), 8.77 (d, J=2.3 Hz, 1H).

Example 13 a)N-(5-Bromo-pyridin-3-ylmethyl)-C,C,C-trifluoro-methanesulfonamide

To a solution of 5-bromo-3-pyridinemethanamine (CAS#135124-70-8, 170 mg,0.65 mmol) in dichloromethane (5 mL) at 0° C. was addeddiisopropylethylamine (0.55 mL, 3.25 mmol) and trifluoromethanesulfonylchloride (0.083 mL, 0.78 mmol). The reaction was stirred at 0° C. for 15minutes and then warmed to room temperature and stirred for anadditional 30 minutes. The reaction was then diluted with saturatedaqueous sodium bicarbonate and brine, and then further diluted withdichloromethane. The layers were separated and the aqueous layer wasextracted two additional times with dichloromethane, and the organiclayers were combined, dried over anhydrous sodium sulfate, filtered, andconcentrated to provideN-(5-bromo-pyridin-3-ylmethyl)-C,C,C-trifluoro-methanesulfonamide without the need for further purification. MS: (ES+) m/z 318.9 (M+H)⁺.

b)C,C,C-Trifluoro-N-[5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridin-3-ylmethyl]-methanesulfonamide

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ES+) m/z 386.0791 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 3.16 (s, 3H), 3.65 (s, 2H), 4.46 (s, 2H), 7.13 (d, J=8.2 Hz, 1H),7.60-7.68 (m, 2H), 7.99 (t, J=2.1 Hz, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.80(d, J=2.3 Hz, 1H), 10.08 (br. s., 1H).

Example 14 a) Propane-2-sulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide

To a solution of 5-bromo-3-pyridinemethanamine (CAS#135124-70-8, 200 mg,0.77 mmol) in DMF (8 mL) at 0° C. was added sodium hydride (60% oildispersion, 150 mg, 3.8 mmol) followed by isopropylsulfonyl chloride(0.13 mL, 1.16 mmol). The reaction was stirred for 30 minutes and thendiluted with brine and dichloromethane. The pH of the aqueous layer wasadjusted to ca. 7 by the addition of acetic acid and the layers wereseparated. The aqueous layer was extracted two additional times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated to providepropane-2-sulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide without theneed for further purification; MS: (ES+) m/z 292.9 (M+H)⁺.

b) Propane-2-sulfonic acid[5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridin-3-ylmethyl]-amide

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ES+) m/z 359.1303 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.24 (d, J=6.8 Hz, 6H), 3.12-3.21 (m, 1H), 3.31 (s, 3H), 3.65 (s,2H), 4.28 (s, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.67 (s, 1H),8.01 (t, J=2.2 Hz, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.3 Hz, 1H).

Example 15 a) 1-(5-Bromo-pyridine-3-ylmethyl)-3-isopropyl-urea N

To a solution of the hydrochloride salt of 5-bromo-3-pyridinemethanamine(CAS#135124-70-8, 176 mg, 0.65 mmol) in 1,4-dioxane (10 mL) at roomtemperature was added diisopropylethylamine (0.550 mL, 3.27 mmol)followed by isopropyl isocyanate (CAS#1795-48-8, 0.13 mL, 1.3 mmol). Thereaction was then heated to 80° C. and stirred for 15 minutes. Thereaction was then cooled to room temperature, quenched with methanol,and stirred for an additional 15 minutes. The resulting solution wasthen concentrated in vacuo to near dryness, and diluted withdichloromethane and brine. The layers were separated and the aqueouslayer was extracted two additional times. The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated to furnish 1-(5-bromo-pyridin-3-ylmethyl)-3-isopropyl-ureawithout the need for further purification; MS: (ES+) m/z 271.9 (M+H)⁺.

b)1-isopropyl-3-[5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridin-3-ylmethyl]-urea

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ES+) m/z 339.1825 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.04 (d, J=6.6 Hz, 6H), 3.16 (s, 3H). 3.63 (s, 2H), 3.65-3.72 (m,1H), 4.19-4.33 (m, 2H), 5.84 (d, J=7.6 Hz, 1H), 6.29 (t, J=6.3 Hz, 1H),7.11 (d, J=8.8 Hz, 1H), 7.50-7.70 (m, 2H), 7.87 (t, J=2.1 Hz, 1H), 8.40(d, J=2.0 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H)

Example 16 a) 2-(5-Bromo-pyridin-3-yl)-propan-2-ol

To a solution of 5-bromo-nicotinoyl chloride (900 mg, 4.1 mmol) in THF(18 mL) at −78° C. was added a 3.0 M solution of methylmagnesium bromidein diethyl ether (5.44 mL, 16.3 mmol). The reaction was stirred for 20minutes and then quenched with saturated aqueous ammonium chloride. Thereaction was then brought to room temperature, diluted with brine andethyl acetate and the layers were separated. The aqueous layer wasextracted two additional times with ethyl acetate, and the organiclayers were combined, dried over anhydrous sodium sulfate, filtered, andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-heptane, 0 to 100%) to afford2-(5-bromo-pyridin-3-yl)-propan-2-ol; MS: (ES+) m/z 216.0 (M+H)⁺.

b)5-[5-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ESI) m/z 283.1445 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.50 (s, 6H), 3.16 (s, 3H), 3.63 (s, 2H), 5.27 (s, 1H), 7.10 (d,J=8.59 Hz, 1H), 7.62-7.68 (m, 2H), 8.04 (t, J=2.15 Hz, 1H), 8.63 (d,J=2.02 Hz, 1H), 8.69 (d, J=2.15 Hz, 1H).

Example 17 a) 3-Bromo-5-(1-methoxy-1-methyl-ethyl)-pyridine

To a solution of 2-(5-bromo-pyridin-3-yl)-propn-2-ol, prepared asdescribed in Example 16a (120 mg, 0.55 mmol) in THF (3 mL) at −20° C.was added potassium bis(trimethylsilyl)amide (0.5 M in toluene, 1.45 mL,0.72 mmol), followed by iodomethane (0.042 mL, 0.67 mmol). The reactionwas permitted to warm to room temperature and stirred for 30 minutes.The reaction was then quenched with ammonium hydroxide and diluted withbrine and dichloromethane and the layers were separated. The aqueouslayer was extracted two additional times with dichloromethane, and theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and concentrated. The resulting residue was purified by silicagel flash chromatography (ethyl acetate-heptane, 0 to 100%) to afford3-bromo-5-(1-methoxy-1-methyl-ethyl)-pyridine; MS: (ES+) m/z 230.2(M+H)⁺.

b)5-[5-(1-Methoxy-1-methyl-ethyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ES+) m/z 297.1601 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.54 (s, 6H), 3.06 (s, 3H), 3.17 (s, 3H), 3.64 (s, 2H), 7.11 (d,J=8.6 Hz, 1H), 7.62-7.75 (m, 2H), 7.94 (t, J=2.3 Hz, 1H), 8.56 (d,J=2.37 Hz, 1H), 8.75 (d, J=2.3 Hz, 1H).

Example 18 a) 3-Bromo-5-isopropenyl-pyridine

To a solution of 2-(5-bromo-pyridin-3-yl)-propan-2-ol, prepared asdescribed in Example 16a (200 mg, 0.93 mmol) in dichloromethane (8 mL)at 0° C. was added diisopropylethylamine (0.63 mL, 3.7 mmol) followed bymethanesulfonyl chloride (0.14 mL, 1.85 mmol). After 5 minutes thereaction was place at room temperature and stirred for an additionalhalf hour. The reaction was quenched with saturated aqueous sodiumbicarbonate, diluted with brine and ethyl acetate and the layers wereseparated. The aqueous layer was extracted two additional times withethyl acetate, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated. The resultingresidue was purified by silica gel flash chromatography (ethylacetate-heptane, 0 to 50%) to furnish 3-bromo-5-isopropenyl-pyridine;MS: (ES+) m/z 198.0 (M+H)⁺.

b) 5-(5-isopropenyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ES+) m/z 265.1339 (M+H)⁺.

c) 5-(5-isopropyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To a solution of5-(5-isopropenyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one (26.5mg, 0.10 mmol) in methanol (10 mL) was added 10% palladium on carbon (55mg, 0.1 mmol). The atmosphere over the reaction mixture was evacuatedand the reaction was placed under an atmosphere of hydrogen gas via aballoon. The reaction was stirred for 15 minutes and then filteredthrough a pad of Celite®. The filtrate was concentrated and theresulting residue was purified by silica gel flash chromatography (ethylacetate-heptane, 10 to 100%) to provide5-(5-isopropyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS:(ES+) m/z 267.1500 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (d,J=7.0 Hz, 6H), 2.95-3.06 (m, 1H), 3.16 (s, 3H), 3.63 (s, 2H), 7.10 (d,J=8.6 Hz, 1H), 7.59-7.71 (m, 2H), 7.88 (t, J=2.1 Hz, 1H), 8.42 (d, J=2.0Hz, 1H), 8.67 (d, J=2.2 Hz, 1H).

Example 19 a) 5-Bromo-4-methyl-pyridine-3-sulfonic acid dimethylamide

To a solution of 5-bromo-pyridine-3-sulfonic acid dimethylamide (CAS#896160-99-9, 100 mg, 0.377 mmol) in THF (3.8 ml) at −78° C. was addedlithium diisopropylamide (0.5 M solution in THF, 0.85 mL, 0.42 mmol).The reaction was stirred for 15 minutes, at which time iodomethane(0.030 mL, 0.48 mmol) was added. The reaction was stirred for anadditional 15 minutes and was then quenched with saturated aqueousammonium chloride. Next, the reaction was diluted with water,dichloromethane, and saturated aqueous sodium bicarbonate. The layerswere separated and aqueous layer was extracted two additional times withdichloromethane. The organic layers were combined, dried over anhydroussodium sulfate, filtered, and concentrated. The resulting residue waspurified by semi-preparative reverse phase HPLC (20 to 90%acetonitrile/water w/0.1% NH₄OH) to furnish5-bromo-4-methyl-pyridine-3-sulfonic acid dimethylamide; MS: (ES+) m/z279.0 (M+H)⁺.

b)4-Methyl-5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridine-3-sulfonicacid dimethylamide

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ES+) m/z 346.1224 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δppm 2.57 (s, 3H), 2.96 (s, 6H), 3.28 (s, 3H), 3.61 (s, 2H), 6.94 (d,J=8.1 Hz, 1H), 7.12-7.25 (m, 2H), 8.59 (s, 1H), 8.96 (s, 1H).

Example 20 a) (5-Bromo-pyridin-3-yl)-cyclopropyl-methanol

To a solution of 3-bromo-5-pyridinecarboxaldehyde (651 mg, 3.50 mmol) inTHF (20 ml) at −78° C. was added cyclopropylmagnesium bromide (0.5M inTHF, 7.49 ml, 3.74 mmol). After 10 minutes, additionalcyclopropylmagnesium bromide (0.5M in THF, 3.0 mL, 1.5 mmol) was added.After stirring for an additional five minutes the reaction was quenchedwith saturated aqueous ammonium chloride. The resulting mixture wasdiluted with dichloromethane and water and the layers were separated.The aqueous layer was extracted two additional times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 7%) to afford(5-bromo-pyridin-3-yl)-cyclopropyl-methanol; MS: (ES+) m/z 228.2 (M+H)⁺.

b) (R)- and(S)-5-[5-(Cyclopropyl-hydroxy-methyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one

The above compound was prepared in a similar fashion as described inExample 4; HRMS: (ES+) m/z 296.1452 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δppm 0.43-0.61 (m, 2H), 0.62-0.82 (m, 2H), 1.19-1.35 (m, 1H), 2.05-2.16(m, 1H), 3.28 (s, 3H), 3.62 (s, 2H), 4.14 (d, J=8.3 Hz, 1H), 6.94 (d,J=8.1 Hz, 1H), 7.51 (s, 1H), 7.55 (d, J=8.1 Hz, 1H), 8.01 (br. s., 1H),8.63 (d, J=1.8 Hz, 1H).

Resolution of the enantiomers of the title compound was achieved bychiral HPLC using a ChiralPak AS-H column with a 1:1 ethanol-heptanemobile phase to provide (R)- or(S)-5-[5-(Cyclopropyl-hydroxy-methyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one(t_(r)=11.5 min) and (R)- or(S)-5-[5-(Cyclopropyl-hydroxy-methyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one(t_(r)=13.8 min).

Example 20c (R)- and(S)-5-[5-(1-Hydroxy-propyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one

The above compound was prepared in a similar fashion as described inExample 20; HRMS: (ES+) m/z 283.1446 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δppm 1.00 (t, J=7.45 Hz, 3H), 1.81-1.96 (m, 2H), 2.05 (br. s., 1H), 3.28(s, 3H), 3.62 (s, 2H), 4.78 (t, J=6.57 Hz, 1H), 6.94 (d, J=8.08 Hz, 1H),7.51 (s, 1H), 7.54 (d, J=8.08 Hz, 1H), 7.93 (t, J=2.02 Hz, 1H), 8.55 (d,J=2.02 Hz, 1H), 8.74 (d, J=2.27 Hz, 1H).

Resolution of the enantiomers of the title compound was achieved bychiral HPLC using a ChiralPak AS-H column with a 1:1 ethanol-heptanemobile phase provides (R)- or(S)-5-[5-(1-Hydroxy-propyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one(t_(r)=25.8 min) and (R)- or(S)-5-[5-(1-Hydroxy-propyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one(t_(r)=31.2 min).

Example 20d (R)- and(S)-5-[5-(1-Hydroxy-ethyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one

The above compound was prepared in a similar fashion as described inExample 20; HRMS: (ES+) m/z 269.1288 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δppm 1.61 (d, J=6.57 Hz, 3H), 2.13 (br. s., 1H), 3.29 (br. s., 3H), 3.63(s, 2H), 5.09 (q, 1H), 6.95 (d, J=7.96 Hz, 1H), 7.52 (s, 1H), 7.54 (d,J=8.08 Hz, 1H), 8.01 (s, 1H), 8.60 (br. s., 1H), 8.74 (br. s., 1H).

Resolution of the enantiomers of the title compound was achieved bychiral supercritical fluid chromatography (SFC) using a ChiralPak IAcolumn with a 1:3 methanol-supercritical CO₂ mobile phase at 150 bar ofpressure to provide (R)- or(S)-5-[5-(1-Hydroxy-ethyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one(t_(r)=6.7 min) and (R)- or(S)-5-[5-(1-Hydroxy-ethyl)-pyridin-3-yl]-1-methyl-1,3-dihydro-indol-2-one(t_(r)=10.6 min).

Example 21 5-(5-Bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one(1.0 g, 3.66 mmol), prepared as described in Example 3a, was added3,5-dibromopyridine (2.6 g, 11 mmol), 1,2-dimethoxyethane (10.0 mL), and2 M aqueous sodium carbonate (4.00 mL, 8.0 mmol). The reaction mixturewas degassed and placed under an argon atmosphere, at which time resinbound tetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (2.0 g, 0.220 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 120° C. for 3 hours. Thereaction mixture was cooled to room temperature, diluted withdichloromethane, and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 3.55%) to furnish5-(5-bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI)m/z 303.0133 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.27 (s, 3H), 3.62(s, 2H), 6.94 (d, J=—8.1 Hz, 1H), 7.48 (s, 1H), 7.50 (d, J=8.1 Hz, 1H),8.01 (t, J=1.9 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.73 (d, J=1.6 Hz, 1H).

Example 225-(5-Cyclopropyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To 5-(5-bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one, preparedas described in Example 21, (100 mg, 0.330 mmol) was added potassiumcyclopropyltrifluoroborate (50 mg, 0.35 mmol), THF (2 mL), water, (0.66mL), and tripotassium phosphate (245 mg, 1.155 mmol). The reactionmixture was degassed and placed under an argon atmosphere, and then[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) complexedwith dichloromethane (CAS#72287-26-4 13.5 mg, 0.016 mmol) was added. Thereaction vessel was sealed and was heated by microwave irradiation at125° C. for 85 minutes. The reaction mixture was cooled to roomtemperature, diluted with dichloromethane and filtered through glasswool. The filtrate was further diluted with saturated aqueous sodiumbicarbonate and the layers were separated. The aqueous layer wasextracted two times with dichloromethane, and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-dichloromethane, 0 to 100%) to afford5-(5-cyclopropyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS:(ESI) m/z 265.1345 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.72-0.89 (m,2H), 1.03-1.19 (m, 2H), 1.85-2.11 (m, 1H), 3.27 (s, 3H), 3.61 (s, 2H),6.92 (d, J=8.1 Hz, 1H), 7.39-7.61 (m, 3H), 8.38 (d, J=1.8 Hz, 1H), 8.60(d, J=2.0 Hz, 1H).

Example 23 5-[3,3′]Bipyridinyl-5-yl-1-methyl-1,3-dihydro-indol-2-one

To 5-(5-bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one prepared asdescribed in Example 21, (100 mg, 0.330 mmol) was added 3-pyridineboronic acid (52.7 mg, 0.429 mmol), 1,2-dimethoxyethane (3 mL), and 2 Maqueous sodium carbonate (0.429 mL, 0.858 mmol). The reaction mixturewas degassed and placed under an argon atmosphere, at which time resinbound tetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (150 mg, 0.016 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 120° C. for 2.5 hours. Thereaction mixture was cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane, 1 to 8%) to furnish5-[3,3′]bipyridinyl-5-yl-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI)m/z 302.1301 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.29 (s, 3H), 3.64(s, 2H), 6.97 (d, J=8.1 Hz, 1H), 7.46 (dd, J=7.5, 4.9 Hz, 1H), 7.53-7.62(m, 2H), 7.92-7.99 (m, 1H), 8.02 (t, J=2.1 Hz, 1H), 8.71 (dd, J=4.8, 1.5Hz, 1H), 8.81 (d, J=2.3 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.93 (d, J=1.8Hz, 1H).

Example 24 1-Ethyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one

To 5-bromo-1-ethyl-1,3-dihydro-indol-2-one (CAS#41192-37-4, 100 mg, 0.42mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 50.2 mg, 0.41mmol), 1,2-dimethoxyethane (2.5 mL), and 2 M aqueous sodium carbonate(0.410 mL, 0.82 mmol). The reaction mixture was degassed and placedunder an argon atmosphere, at which timetetrakis(triphenylphosphine)palladium(0) (12 mg, 0.026 mmol)] was added.The reaction vessel was sealed and was heated by microwave irradiationat 100° C. for 45 minutes. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate and brine and the layers wereseparated. The aqueous layer was extracted two times with ethyl acetate,and the organic layers were combined, dried over anhydrous sodiumsulfate, filtered and concentrated. The resulting residue was purifiedby silica gel flash chromatography (ethyl acetate-heptane, 10 to 100%)to afford 1-ethyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) mr 239.1190 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.32 (t, J=7.2 Hz, 3H),3.61 (s, 2H), 3.83 (q, J=7.3 Hz, 2H), 6.96 (d, J=8.1 Hz, 1H), 7.38 (dd,J=7.3, 4.8 Hz, 1H), 7.46-7.57 (m, 2H), 7.78-7.95 (m, 1H), 8.58 (dd,J=4.7, 1.4 Hz, 1H), 8.83 (d, J=1.8 Hz, 1H).

Example 25 1-Cyclopropyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one

To 5-pyridin-3-yl-1,3-dihydro-indol-2-one (CAS#220904-98-3, 63 mg, 0.3mmol) was added freshly prepared tricyclopropyl-bismuthine [(J. Am.Chem. Soc., 2007, 129, 44-45), CAS#925430-09-7, 250 mg, 0.75 mmol],Cu(OAc)₂ (82 mg, 0.45 mmol,) and dichloromethane (3 ml). The reactionmixture was degassed by sparging with argon for 5 min. Then pyridine(0.073 ml, 0.9 mmol) was added and the reaction was heated at 75°C. for1.5 hr. The reaction mixture was cooled to room temperature and thendirectly loaded on to a silica gel flash chromatography column. The1-cyclopropyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one was eluted via agradient of ethyl acetate-heptane (0 to 100%); HRMS: (ESI) m/z 251.1173(M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.88-1.01 (m, 2H), 1.07-1.19 (m,2H), 2.60-2.76 (m, 1H), 3.60 (s, 2H), 7.22-7.31 (m, 1H), 7.49 (s, 1H),7.55 (d, J=−8.5 Hz, 1H), 7.81 (br. s., 1H), 8.36 (d, J=7.7 Hz, 1H), 8.63(br. s., 1H), 8.92 (br. s., 1H).

Example 26 a) 4-Chloro-1-methyl-1,3-dihydro-indol-2-one

To a solution of 4-chloroisatin (CAS#6344-05-4, 3.64 g, 20.0 mmol) inacetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol)followed by iodomethane (2.75 mL, 44.0 mmol). The reaction was thenplaced at 60° C. and stirred for 40 minutes. The reaction was thencooled to room temperature, filtered and concentrated to 10% of theoriginal volume. The reaction was then diluted with dichloromethane,water, and brine. The layers were separated and the aqueous layer wasextracted two additional times with dichloromethane. The organicextracts were combined, dried over anhydrous sodium sulfate filtered,and concentrated to provide 4-chloro-1-methyl-1H-indole-2,3-dione as anorange solid without the need for further purification. The4-chloro-1-methyl-1H-indole-2,3-dione (1.55 g, 7.92 mmol) was thentreated with hydrazine hydrate (14.8 mL, 475 mmol). The reaction wasthen placed at 70° C. and heated to 130° C. over 20 minutes. Thereaction was stirred at 130° C. for 45 minutes, at which time thereaction was placed at room temperature and cooled by the addition ofice. Once the reaction was cooled to room temperature it was dilutedwith dichloromethane and water and the layers were then separated. Theaqueous layer was extracted an additional two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane 0 to 2%) to afford4-chloro-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 182.0 (M+H)⁺.

b) 5-Bromo-4-chloro-1-methyl-1,3-dihydro-indol-2-one

Water (25 mL) was added to 4-chloro-1-methyl-1,3-dihydro-indol-2-one(1.25 g, 6.9 mmol) and the resulting mixture was placed at 68° C. In aseparate flask potassium bromide (1.64 g, 13.8 mmol) in water (25 mL)was treated with bromine (0.35 mL, 6.9 mmol), the resulting orangesolution was added dropwise to the4-chloro-1-methyl-1,3-dihydro-indol-2-one mixture over ca. 20 minutes.The resulting heterogeneous mixture was permitted to stir at 68° C. foran additional 5 minutes and then cooled to room temperature. Thereaction was then diluted with dichloromethane and saturated aqueoussodium bicarbonate. The solution was then further diluted with saturatedaqueous sodium thiosulfate. The layers were separated and the aqueouslayer was extracted two additional times with dichloromethane. Theorganic extracts were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The resulting residue was preadsorbed ontosilica gel and purified by silica gel flash chromatography (ethylacetate-heptane 15 to 50%) to provide5-bromo-4-chloro-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 259.9(M+H)⁺.

c) 4-Chloro-1-methyl-3-pyridin-3-yl-1,3-dihydro-indol-2-one

To 5-bromo-4-chloro-1-methyl-1,3-dihydro-indol-2-one (78 mg, 0.3 mmol)was added 3-pyridine boronic acid (CAS#1692-25-7, 50.2 mg, 0.41 mmol),1,2-dimethoxyethane (2.5 mL) and 2 M aqueous sodium carbonate (0.410 mL,0.82 mmol). The reaction mixture was degassed and placed under an argonatmosphere, at which time resin boundtetrakis(triphenylphosphine)paladium(0), specifically polystyrenetriphenylphosphine palladium (0) (PS—PPh₃-Pd(0) (Biotage), 0.09 mmol/gloading, (167 mg, 0.015 mmol)) was added. The reaction vessel was sealedand was heated by microwave irradiation at 100° C. for 75 minutes. Thereaction mixture was cooled to room temperature, diluted withdichloromethane and saturated aqueous sodium carbonate, and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography (ethylacetate-heptane, 40 to 100%) to afford4-chloro-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI)m/z 259.0636 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.27 (s, 3H), 3.62(s, 2H), 6.85 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.38-7.48 (m,1H), 7.85 (d, J=7.8 Hz, 1H), 8.64 (dd, J—=4.9, 1.6 Hz, 1H), 8.69 (d,J=2.3 Hz, 1H).

Example 27 a)4-Chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one

To a solution of 5-bromo-4-chloro-1-methyl-1,3-dihydro-indol-2-one (521mg, 2.00 mmol), prepared as described in Example 26b, in DMSO (8 mL) wasadded bis(pinacolato)diboron (559 mg, 2.2 mmol), and potassium acetate(589 mg, 6.0 mmol). Next[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(1) complexedwith dichloromethane (CAS#72287-26-4, 65 mg, 0.08 mmol) was added. Thereaction mixture was degassed by bubbling argon through the solution for3 minutes. The reaction was then heated at 80° C. for 20 hr. Thereaction was then poured into ice-water and extracted three times withdiethyl ether. The organic extracts were combined, washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Theresulting residue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 2%) to afford4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one;MS: (ES+) m/z 308.2 (M+H)⁺.

b) 4-Chloro-5-(5-ethoxy-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one(95 mg, 0.31 mmol) was added 3-bromo-5-ethoxy-pyridine (CAS#17117-17-8,69 mg, 0.34 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodiumcarbonate (0.390 mL, 0.77 mmol). The reaction mixture was degassed andplaced under an argon atmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (140 mg, 0.015 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 115° C. for 3 hours. Thereaction mixture was then cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 3%) to furnish4-chloro-5-(5-ethoxy-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 303.0901 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.48 (t,J=6.9 Hz, 3H), 3.26 (s, 3H), 3.61 (s, 2H), 4.15 (q, J=6.9 Hz, 2H), 6.84(d, J=8.1 Hz, 1H), 7.28-7.33 (m, 2H), 8.26 (d, J=1.8 Hz, 1H), 8.32 (d,J=2.8 Hz, 1H).

Example 285-(5-Bromo-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-one

To4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one(525 mg, 1.71 mmol), prepared as described in Example 27a, was added3,5-dibromopyridine (CAS#625-92-3, 1.2 g, 5.1 mmol), 1,2-dimethoxyethane(5.0 mL), and 2 M aqueous sodium carbonate (2.05 mL, 4.1 mmol). Thereaction mixture was degassed and placed under an argon atmosphere, atwhich time resin bound tetrakis(triphenylphosphine)palladium(0),specifically polystyrene triphenylphosphine palladium (0) [PS—PPh₃-Pd(0)(Biotage), 0.11 mmol/g loading, (0.93 g. 0.10 mmol)] was added. Thereaction vessel was sealed and was heated by microwave irradiation at120° C. for 3.5 hours. The reaction mixture was cooled to roomtemperature, diluted with dichloromethane and filtered through glasswool. The filtrate was further diluted with saturated aqueous sodiumbicarbonate and the layers were separated. The aqueous layer wasextracted two times with dichloromethane, and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethanol-dichloromethane. 0 to 3.55%) to furnish5-(5-bromo-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 336.9753 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.27 (s,3H), 3.62 (s, 2H), 6.85 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H),7.95-8.04 (m, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.70 (d, J=2.3 Hz, 1H).

Example 295-(5-Amino-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-one

To4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one,prepared as described in Example 27a, (85 mg, 0.276 mmol) was added3-amino-5-bromopyridine (CAS#13535-01-8, 53 mg, 0.304 mmol),tripotassium phosphate (147 mg, 0.691 mmol) and DMF (2.5 mL). Thereaction mixture was degassed and placed under an argon atmosphere, atwhich time resin bound tetrakis(triphenylphosphine)palladium(0),specifically polystyrene triphenylphosphine palladium (0) [PS—PPh₃-Pd(0)(Biotage), 0.11 mmol/g loading, (126 mg, 0.014 mmol)] was added. Thereaction vessel was sealed and was heated by microwave irradiation at115° C. for 75 minutes. The reaction mixture was then cooled to roomtemperature, diluted with dichloromethane and filtered through glasswool. The filtrate was further diluted with saturated aqueous sodiumbicarbonate and the layers were separated. The aqueous layer wasextracted two times with dichloromethane, and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethanol-dichloromethane, 0 to 5%) to furnish5-(5-amino-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 274.0742 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.26 (s,3H), 3.60 (s, 2H). 3.88 (br. s., 2H), 6.82 (d, J=7.8 Hz, 1H), 7.10 (br.s., 1H), 7.29 (d, J=8.1 Hz, 1H), 8.07 (d, J=1.5 Hz, 1H), 8.15 (br. s.,1H).

Example 30 a) 3-Bromo-5-vinyl-pyridine

To a solution of methyltriphenylphosphonium bromide (2.97 g, 8.33 mmol)in THF (45 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes,2.7 mL, 6.75 mmol). The resulting yellow reaction mixture was stirredfor 30 min at −78° C. In a separate flask THF (9 mL) was added to5-bromonicotinaldehyde (CAS#113118-81-3, 837 mg, 4.5 mmol). Theresulting 5-bromonicotinaldehyde solution was the transferred, viacannula, to the phosphonium ylide mixture followed by a 2 mL THF wash.The reaction was allowed to warm to room temperature over 120 minutesand then permitted to stir for an additional 30 minutes. The reactionwas then quenched with saturated aqueous sodium bicarbonate and dilutedwith ethyl acetate. The layers were separated and the organic layer waswashed with saturated aqueous sodium bicarbonate. The organic layer wasconcentrated to near dryness and the resulting residue was then dilutedwith ethyl acetate and 1M sodium bisulfate and the layers wereseparated. The organic layer was extracted two additional times with 1Msodium bisulfate. The aqueous layers were combined, diluted withdichloromethane, and neutralized via the careful addition of saturatedaqueous sodium bicarbonate and solid sodium carbonate. The layers wereseparated and the now basic aqueous layer was extracted three additionaltimes with dichloromethane. The dichloromethane layers were combined,dried over anhydrous sodium sulfate, filtered and concentrated. Theresulting residue was purified by silica gel flash chromatography (ethylacetate-dichloromethane, 0 to 16%) to furnish 3-bromo-4-vinyl-pyridine;MS: (ES+) m/z 183.9 (M+H)⁺

b) 4-Chloro-1-methyl-5-(5-vinyl-pyridin-3-yl)-1,3-dihydro-indol-2-one

The above compound was prepared in a similar fashion as described inExample 27; MS: (ES+) m/z 285.0 (M+H)⁺

c) 4-Chloro-5-(5-ethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To a solution of4-chloro-1-methyl-5-(5-vinyl-pyridin-3-yl)-1,3-dihydro-indol-2-one (70mg, 0.246 mmol) in ethanol (5 mL) was added 10% palladium on carbon (39mg, 0.037 mmol). The atmosphere over the reaction mixture was evacuatedand the reaction was placed under an atmosphere of hydrogen gas via aballoon. The reaction was stirred for 25 minutes. The reaction mixturewas then filtered through a plug of Celite® and the filtrate was thenconcentrated to dryness. The resulting residue was purified by silicagel flash chromatography (ethanol-dichloromethane, 0 to 5%) to afford4-chloro-5-(5-ethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one.HRMS: (ESI) m/z 287.0946 (M+H)+; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.33 (t,J=7.6 Hz, 3H), 2.76 (q, J=7.6 Hz, 2H), 3.27 (s, 3H), 3.61 (s, 2H), 6.85(d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 8.45-8.57 (m,2H).

Example 314-Chloro-5-(5-cyclopropyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To 5-(5-bromo-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-oneprepared as described in Example 28, (85 mg, 0.25 mmol) was addedpotassium cyclopropyltrifluoroborate (41 mg, 0.38 mmol), THF (2 mL)water, (0.66 mL), and tripotassium phosphate (187 mg, 0.88 mmol). Thereaction mixture was degassed and placed under an argon atmosphere, andthen [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)complexed with dichloromethane (CAS#72287-264 10.3 mg, 0.013 mmol) wasadded. The reaction vessel was sealed and was heated by microwaveirradiation at 125° C. for 4 h. The reaction mixture was cooled to roomtemperature and diluted with dichloromethane and saturated aqueoussodium bicarbonate and the layers were separated. The aqueous layer wasextracted two times with dichloromethane, and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered through a pad ofCelite®, and concentrated. The resulting residue was purified by silicagel flash chromatography (ethyl acetate-dichloromethane, 0 to 100%) toafford4-chloro-5-(5-cyclopropyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 299.0955 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.78-0.82(m, 2H), 1.01-1.18 (m, 2H), 1.94-2.04 (m, 1H), 3.26 (s, 3H), 3.61 (s,2H), 6.83 (d, J=7.8 Hz, 1H), 7.26-7.31 (m, 1H), 7.44 (br. s., 1H),8.36-8.54 (m, 2H).

Example 325-[3,3′]Bipyridinyl-5-yl-4-chloro-1-methyl-1,3-dihydro-indol-2-one

To 5-(5-bromo-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-oneprepared as described in Example 28, (100 mg, 0.30 mmol) was added3-pyridine boronic acid (CAS#1692-25-7, 47.3 mg, 0.385 mmol),1,2-dimethoxyethane (3 mL), and 2 M aqueous sodium carbonate (0.385 mL,0.770 mmol). The reaction mixture was degassed and placed under an argonatmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (135 mg, 0.015 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 120° C. for 2.5 hours. Thereaction mixture was cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane, 1 to 8%) to furnish5-[3,3′]bipyridinyl-5-yl-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI)m/z 336.0905 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.18 (s, 3H), 3.68(s, 2H), 7.15 (d, J=8.1 Hz, 1H), 7.50-7.60 (m, 2H), 8.20 (t, J=2.1 Hz,1H), 8.21-8.27 (m, 1H), 8.65 (dd, J=4.7, 1.6 Hz, 1H), 8.68 (d, J=2.0 Hz.1H), 8.97 (d, J=2.1 Hz, 1H), 9.03 (d, J=2.4 Hz, 1H).

Example 33 a) 1,4-Dimethyl-1H-indole

To a solution of 4-methyl-1H-indole (CAS#16096-32-5, 2.82 mL, 22.9 mmol)in THF (100 mL) at 0° C. was added sodium hydride (60% dispersion inoil, 1.37 g, 34.3 mmol). The reaction was permitted to stir for 15minutes at 0° C. and was then warmed to room temperature for 60 minutes.The reaction mixture was then re-cooled to 0° C. and iodomethane (1.86mL, 29.7 mmol) was added. The reaction was then put at room temperatureand permitted to stir for 45 minutes. The reaction was then quenchedwith saturated aqueous ammonium chloride and concentrated toapproximately half of its original volume. The mixture was then dilutedwith water and dichloromethane and the layers were separated. Theaqueous layer was then extracted two additional times withdichloromethane. The organic layers were combined, dried over anhydroussodium sulfate, filtered and concentrated. The resulting residue waspurified by silica gel flash chromatography (ethyl acetate-heptane 0 to30%) to afford 1,4-dimethyl-1H-indole; ¹H NMR (400 MHz, CDCl₃) δ ppm2.57 (s, 3H), 3.80 (s, 3H), 6.51 (d, J=3.0 Hz, 1H), 6.93 (d, J=6.7 Hz,1H), 7.06 (d, J=3.0 Hz, 1H), 7.13-7.21 (m, 2H).

b) 5-Bromo-1,4-dimethyl-1,3-dihydro-indol-2-one

To a solution of 1,4-dimethyl-1H-indole, (200 mg, 1.38 mmol) intert-butanol (8 mL) was added water (4 mL) and the mixture was put at50° C. In a separate flask was added potassium bromide (1.6 g, 13.8mmol) followed by water (11 mL) and bromine (0.36 mL, 6.9 mmol). Nextthe bromine solution (8 mL) was added dropwise to the1,4-dimethyl-1H-indole mixture. After the addition was complete thetemperature of the reaction was elevated to 70° C. for 30 min. Thereaction was cooled to room temperature and diluted with dichloromethaneand saturated aqueous sodium bicarbonate. The solution was then furtherdiluted with saturated aqueous sodium thiosulfate. The layers wereseparated and the aqueous layer was extracted two additional times withdichloromethane. The organic extracts were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resulting solidwas tritrated with diethyl ether and one half of the solid, by weight,was then dissolved in acetic acid (2.5 mL). Zinc dust (62 mg, 0.94 mmol)was then added. After 10 minutes the reaction mixture was filteredthrough a pad of Celite® and diluted with dichloromethane. The resultingsolution was cooled to 0° C. and neutralized via the cautious additionof 2 N aqueous sodium hydroxide and saturated aqueous sodiumbicarbonate. The resulting layers were separated and the aqueous layerwas extracted two additional times with dichloromethane. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-heptane 15 to 80%) to afford5-bromo-1,4-dimethyl-1,3-dihydro-indol-2-one; ¹H NMR (400 MHz, CDCl₃) δppm 2.32 (s, 3H), 3.19 (s, 3H), 3.47 (s, 2H), 6.56 (d, J=8.1 Hz, 1H),7.48 (d, J=8.1 Hz, 1H).

c) 1,4-Dimethyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one

To 1,4-dimethyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one (85 mg, 0.35mmol) was added 3-pyridineboronic acid (CAS#1692-25-7, 52 mg, 0.43mmol), 1,2-dimethoxyethane (3 mL), and 2 M aqueous sodium carbonate(0.44 mL, 0.89 mmol). The reaction mixture was degassed and placed underan argon atmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (161 mg, 0.018 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 120° C. for 2 hours. Thereaction mixture was cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography (ethylacetate-dichloromethane, 15 to 100%) to afford1,4-dimethyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z239.1183 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.20 (s, 3H), 3.26 (s,3H), 3.50 (s, 2H), 6.79 (d, J=8.1 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H),7.34-7.51 (m, 1H), 7.71-7.73 (m, 1H), 8.54-8.69 (m, 2H).

Example 34 a)1,4-Dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one

To a solution of 5-bromo-1,4-dimethyl-1,3-dihydro-indol-2-one, preparedas described in Example 33b, (550 mg, 2.3 mmol), in DMSO (9.5 mL) wasadded bis(pinacolato)diboron (640 mg, 2.5 mmol), and potassium acetate(674 mg, 6.9 mmol). Next[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) complexedwith dichloromethane (CAS#72287-26-4, 94 mg, 0.115 mmol) was added. Thereaction mixture was degassed by bubbling argon through the solution for3 minutes. The reaction was then heated at 85° C. for 14.5 hr. Thereaction was then cooled to room temperature, diluted with diethyl etherand filtered through Celite®. The filtrate was then diluted with waterand the layers were separated. The aqueous layer was extracted twoadditional times with diethyl ether. The organic extracts were combined,washed with brine, dried over anhydrous magnesium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-dichloromethane, 0 to 5%) to afford1,4-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one;MS: (ES+) m/z 288.3 (M+H)⁺.

b) 5-(5-Hydroxymethyl-pyridin-3-yl)-1,4-dimethyl-1,3-dihydro-indol-2-one

To1,4-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one(85 mg, 0.30 mmol) was added (5-bromo-pyridin-3-yl)-methanol(CAS#37669-64-0, 61 mg, 0.33 mmol), 1,2-dimethoxyethane (3.0 mL), and 2M aqueous sodium carbonate (0.370 mL, 0.74 mmol). The reaction mixturewas degassed and placed under an argon atmosphere, at which time resinbound tetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (135 mg, 0.015 mmol)] was added. The reaction vessel was sealedwas heated by microwave irradiation at 120° C. for 3 hours. The reactionmixture was then cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was partially purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 7.5%). Further purification wasaccomplished via reverse phase HPLC (10 to 40% acetonitrile/water w/0.1%NH₄OH) to furnish5-(5-hydroxymethyl-pyridin-3-yl)-1,4-dimethyl-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 269.1288 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.14(s, 3H), 3.15 (s, 3H), 3.56 (s, 2H). 4.60 (s, 2H), 5.35 (br. s., 1H),6.93 (d, J=7.8 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.65 (t, J=2.1 Hz, 1H),8.40 (d, J=2.3 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H).

Example 35 5-(5-Bromo-pyridin-3-yl)-1,4-dimethyl-1,3-dihydro-indol-2-one

To1,4-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one,prepared as described in Example 34a (90 mg, 0.31 mmol) was added3,5-dibromopyridine (CAS#625-92-3, 223 mg, 0.940 mmol),1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.376mL, 0.75 mmol). The reaction mixture was degassed and placed under anargon atmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (171 mg, 0.019 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 120° C. for 2 hours. Thereaction mixture was then cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography (ethylacetate-dichloromethane, 0 to 65%) to furnish5-(5-bromo-pyridin-3-yl)-1,4-dimethyl-1,3-dihydro-indol-2-one; HRMS:(ESI) m/z 317.0289 (M+H)⁺: ¹H NMR (400 MHz, CDCl₃) δ ppm 2.20 (s, 3H),3.26 (s, 3H). 3.50 (s, 2H), 6.78 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz,1H), 7.82 (t, J=2.0 Hz, 1H), 8.50 (d, J=1.8 Hz, 1H), 8.68 (d, J=2.1 Hz,1H).

Example 36 a) 4-Methoxy-1-methyl-1H-indole

To a solution of 4-methoxy-1H-indole (CAS#4837-90-5, 4.0 g, 27.2 mmol)in THF (100 ml) at 0° C. was added sodium hydride (60% dispersion inoil, 1.63 g, 40.08 mmol). The reaction was stirred for 15 minutes at 0°C. and then put at room temperature for 1 h. The reaction was thenre-cooled to 0° C. and iodomethane (2.209 ml, 35.3 mmol) was added. Thereaction was then put at room temperature and permitted to stir for 45minutes. The reaction was then quenched with saturated aqueous ammoniumchloride and concentrated to approximately half of its original volume.Next, the reaction mixture was diluted with water and dichloromethaneand the layers were separated. The aqueous layer was then extracted twoadditional times with dichloromethane. The organic layers were combined,dried over anhydrous sodium sulfate, filtered and concentrated. Theresulting residue was purified by silica gel flash chromatography (ethylacetate-heptane 0 to 30%) to afford 4-methoxy-1-methyl-1H-indole; MS:(ES+) m/z 162.0 (M+H)⁺.

b) 4-Methoxy-1-methyl-1,3-dihydro-indol-2-one

To a solution of potassium bromide (3986 mg, 33.5 mmol) in water (26.5ml) was added bromine (0.863 ml, 16.75 mmol). A separate flaskcontaining 4-methoxy-1-methyl-1H-indole (900 mg, 5.58 mmol) was chargedwith t-butanol (20.00 ml) and water (20.0 ml). To this flask was added22.5 mL of bromine solution dropwise. The mixture was permitted to stirfor approximately 30 minutes and then was neutralized with saturatedaqueous sodium bicarbonate and quenched with saturated aqueous sodiumthiosulfate. The reaction was then diluted with dichloromethane andsaturated aqueous sodium bicarbonate and the layers were separated. Theaqueous layer was extracted two additional times with dichloromethaneand the organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and concentrated. The resulting residue was dissolvedin 50 mL EtOH and 5 mL of AcOH. The solution was then charged with 10%palladium on carbon (1.2 g, 1.13 mmol). The atmosphere over the reactionmixture was evacuated and the reaction was placed under an atmosphere ofhydrogen gas via a balloon. The reaction was stirred for 18 hours. Thereaction mixture was then filtered through a plug of Celite® and thefiltrate was then concentrated to approximately 25% of its originalvolume. The reaction was then diluted with dichloromethane and saturatedaqueous sodium bicarbonate and the layers were separated. The aqueouslayer was extracted two additional times with dichloromethane and theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and concentrated. The resulting residue was purified by silicagel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford4-methoxy-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 178.0 (M+H)⁺.

c) 5-Bromo-4-methoxy-1-methyl-1,3-dihydro-indol-2-one

To a solution of 4-methoxy-1-methyl-1,3-dihydro-indol-2-one (440 mg,2.483 mmol) in chloroform (25 ml) was added methanol (25.00 ml). Thereaction was put at −10° C. and N-bromosuccinimide (442 mg, 2.483 mmol)was added in three portions over a 30 min interval and the reaction wasthen stirred for 10 minutes. The reaction was then diluted withdichloromethane, saturated aqueous sodium bicarbonate, and saturatedaqueous sodium thiosulfate and the layers were separated. The aqueouslayer was extracted two additional times with dichloromethane and theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and concentrated. The resulting residue was purified by silicagel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford5-bromo-4-methoxy-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 255.8(M+H)⁺.

d) 4-Methoxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one

To 5-bromo-4-methoxy-1-methyl-1,3-dihydro-indol-2-one (105 mg, 0.410mmol) was added 3-pyridineboronic acid (CAS#1692-25-7, 60.5 mg, 0.492mmol), 1,2-dimethoxyethane (3 mL) and 2 M aqueous sodium carbonate(0.513 ml, 1.025 mmol). The reaction mixture was degassed and placedunder an argon atmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (186 mg, 0.021 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 120° C. for 2.25 hours. Thereaction mixture was cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography (ethylacetate-dichloromethane, 20 to 100%) to afford4-methoxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI)m/z 255.1136 (M+H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.20 (s, 3H), 3.66(s, 2H), 3.72 (s, 3H), 6.68 (d, J=8.0 Hz, 1H), 7.28 (d, J-8.0 Hz, 1H),7.38 (dd, J=7.9, 4.9 Hz, 1H), 7.79-7.96 (m, 1H), 8.52 (d, J=4.0 Hz, IH), 8.71 (s, 1H).

Example 37 a)4-Methoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one

To a solution of 5-bromo-4-methoxy-1-methyl-1,3-dihydro-indol-2-one,prepared as described in Example 36c (480 mg, 1.87 mmol), in DMSO (8.5mL) was added bis(pinacolato)diboron (524 mg, 2.06 mmol), and potassiumacetate (552 mg, 6.62 mmol). Next[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) complexedwith dichloromethane (CAS#72287-26-4, 77 mg, 0.094 mmol) was added. Thereaction mixture was degassed by bubbling argon through the solution for3 minutes. The reaction was then heated at 85° C. for 14.5 hr. Thereaction was then cooled to room temperature, diluted with diethyl etherand filtered through Celite®. The filtrate was then diluted with waterand the layers were separated. The aqueous layer was extracted twoadditional times with diethyl ether. The organic extracts were combined,washed with saturated aqueous sodium bicarbonate, dried over anhydrousmagnesium sulfate, filtered and concentrated. The resulting residue waspurified by silica gel flash chromatography (ethylacetate-dichloromethane, 0 to 15%) to afford4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one;MS: (ES+) m/z 304.0 (M+H)⁺.

b) 5-(5-Bromo-pyridin-3-yl)-4-methoxy-1-methyl-1,3-dihydro-indol-2-one

To4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one(80 mg, 0.264 mmol) was added 3,5-dibromopyridine (CAS#625-92-3, 188 mg,0.792 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodiumcarbonate (0.320 mL, 0.63 mmol). The reaction mixture was degassed andplaced under an argon atmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (144 mg, 0.016 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 120° C. for 2 hours. Thereaction mixture was then cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography (ethylacetate-dichloromethane, 10 to 75%) to furnish5-(5-bromo-pyridin-3-yl)-4-methoxy-1-methyl-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 333.0246 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.24 (s,3H), 3.75 (s, 3H), 3.78 (s, 2H), 4.71 (s, 2H), 6.84 (d, J=8.1 Hz, 1H),7.34 (d, J=8.1 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H),8.55 (d, J=2.0 Hz, 1H)

Example 385-(5-Hydroxymethyl-pyridin-3-yl)-4-methoxy-1-methyl-1,3-dihydro-indol-2-one

To4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one,prepared as described in Example 37a (80 mg, 0.264 mmol) was added(5-bromo-pyridin-3-yl)-methanol (CAS#37669-64-0, 55 mg, 0.29 mmol),1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.330mL, 0.66 mmol). The reaction mixture was degassed and placed under anargon atmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (120 mg, 0.013 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 120° C. for 3 hours. Thereaction mixture was then cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was partially purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 10%). Further purification wasaccomplished via reverse phase HPLC (7 to 40% acetonitrile/water w/0.1%NH₄OH) to furnish5-(5-hydroxymethyl-pyridin-3-yl)-4-methoxy-1-methyl-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 285.1240 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 3.24 (s,3H), 3.75 (s, 3H), 3.78 (s, 2H), 4.71 (s, 2H), 6.84 (d, J=8.1 Hz, 1H),7.34 (d, J=8.1 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H),8.55 (d. J=2.0 Hz, 1H)

Example 39 a) 6-Bromo-1-methyl-1,3-dihydro-indol-2-one

To a solution of 6-bromoisatin (CAS#6326-79-0, 4.52 g, 20.0 mmol) inacetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol)followed by iodomethane (2.75 mL, 44.0 mmol). The reaction was thenplaced at 60° C. and stirred for 40 minutes. The reaction was thencooled to room temperature, filtered and concentrated to 10% of theoriginal volume. The reaction was then diluted with dichloromethane,water, and brine. The layers were separated and the aqueous layer wasextracted two additional times with dichloromethane. The organicextracts were combined, dried over anhydrous sodium sulfate filtered andconcentrated to provide 6-bromo-1-methyl-1H-indole-2,3-dione as anorange solid without the need for further purification. The6-bromo-1-methyl-1H-indole-2,3-dione (1.0 g, 4.2 mmol) was then treatedwith hydrazine hydrate (7.0 mL, 225 mmol). The reaction was heated to130° C. and stirred for 80 minutes, at which time the reaction wasplaced at room temperature and cooled by the addition of ice. Once thereaction was cooled to room temperature it was diluted withdichloromethane and water and the layers were separated. The aqueouslayer was extracted an additional two times with dichloromethane, andthe organic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The resulting residue was purified by silicagel flash chromatography (ethanol-dichloromethane 0 to 2%) to afford6-bromo-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 225.9 (M+H)⁺.

b) 1-Methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile

To a solution of 6-bromo-1-methyl-1,3-dihydro-indol-2-one (226 mg, 1.0mmol) in DMF (6.0 mL) was added zinc cyanide (117 mg, 1.0 mmol). Thenthe reaction mixture was degassed and placed under an argon atmosphereand tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.1 mmol) wasadded. The reaction was then placed at 95° C. for 100 minutes, at whichtime it was cooled to room temperature, and diluted with saturatedaqueous sodium bicarbonate and dichloromethane. The layers wereseparated and the aqueous layer was extracted two additional times withdichloromethane. The organic layers were combined, dried over anhydroussodium sulfate, filtered and concentrated. The resulting residue waspurified by silica gel flash chromatography (ethanol-dichloromethane 0to 4%) to furnish 1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile;MS: (ES+) m/z 173.0 (M+H)⁺.

c) 5-Bromo-1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile

Water (9 mL) was added to1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile (110 mg 0.64 mmol)and the resulting mixture was placed at 70° C. In a separate flaskpotassium bromide (462 g, 0.26 mmol) in water (12 mL) was treated withbromine (0.100 mL, 1.94 mmol). 6.0 mL of the orange bromine solution wasadded dropwise to the water and1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile mixture over ca. 20minutes. The resulting heterogeneous mixture was permitted to stir at70° C. for an additional 5 minutes and then cooled to room temperature.The reaction was then diluted with dichloromethane and saturated aqueoussodium bicarbonate. The solution was then further diluted with saturatedaqueous sodium thiosulfate. The layers were separated and the aqueouslayer was extracted two additional times with dichloromethane. Theorganic extracts were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The resulting residue was purified by silicagel flash chromatography (ethanol-dichloromethane 0 to 3.5%) to provide5-bromo-1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile; MS: (ES+)m/z 250.9 (M+H)⁺.

d) 1-Methyl-2-oxo-5-pyridin-3-yl-2,3-dihydro-1H-indole-6-carbonitrile

To 5-bromo-1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile (58 mg,0.23 mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 28 mg, 0.23mmol), 1,2-dimethoxyethane (2.0 mL) and 2 M aqueous sodium carbonate(0.230 mL, 0.46 mmol). The reaction mixture was degassed and placedunder an argon atmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.09 mmol/gloading, (105 mg, 0.009 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 100° C. for 1.75 hours. Thereaction mixture was cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 6%) to afford1-methyl-2-oxo-5-pyridin-3-yl-2,3-dihydro-1H-indole-6-carbonitrile;HRMS: (ESI) m/z 248.0838 (M−H)−; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.30 (s,2H), 3.68 (s, 2H), 7.19 (s, 1H), 7.42 (s, 1H), 7.49-7.58 (m, 1H), 8.02(d, J=7.6 Hz, 1H), 8.72 (dd, J=4.8, 1.1 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H).

Example 40 a) 4-Cyclopropyl-1-methyl-1H-indole-2,3-dione

To a solution of 4-bromo-1-methyl-1,3-dihydro-indol-2-one, prepared in afashion similar as described in Example 39a (CAS#884855-67-8, 1.80 g,7.5 mmol) in THF (24 mL) was added water (8 mL), tripotassium phosphate(5.57 g, 26.3 mmol), and potassium cyclopropyltrifluoroborate (1.501 g,10.50 mmol). The reaction mixture was degassed and placed under anitrogen atmosphere, and then[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) complexedwith dichloromethane (CAS#72287-26-4 184 mg, 0.225 mmol) was added. Thereaction vessel was sealed and was heated by microwave irradiation at130° C. for 4 hours. The reaction mixture was then cooled to roomtemperature, diluted with ethyl acetate and brine and then filteredthrough a pad of Celite®. The layers of the filtrate were separated andthe aqueous layer was extracted two times with ethyl acetate. Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The resulting residue was purified by silicagel flash chromatography (ethyl acetate-heptane, 0 to 100%) to furnish4-cyclopropyl-1-methyl-1H-indole-2,3-dione; MS: (ES+) m/z 202.4 (M+H)⁺.

b) 4-Cyclopropyl-1-methyl-1,3-dihydro-indol-2-one

4-Cyclopropyl-1-methyl-1H-indole-2,3-dione (1.0 g, 4.2 mmol) was treatedwith hydrazine hydrate (7.0 mL, 225 mmol). The reaction was heated to130° C. and stirred for 4 hours, at which time the reaction temperaturewas elevated to 150° C. for another 1.5 hours. The reaction was thenplaced at room temperature and cooled by the addition of ice. Once thereaction was cooled to room temperature it was diluted withdichloromethane and water and the layers were separated. The aqueouslayer was extracted an additional two times with dichloromethane, andthe organic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The resulting residue was purified by silicagel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 188.4(M+H)⁺.

c) 5-Bromo-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one

Water (14 mL) was added to4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one (0.74 g, 3.94 mmol) andthe resulting mixture was placed at 70° C. In a separate flask potassiumbromide (1.03 g, 8.7 mmol) in water (14 mL) was treated with bromine(0.225 mL, 4.3 mmol), the resulting orange solution was added dropwiseto the 4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one mixture over ca.10 minutes. The resulting heterogeneous mixture was permitted to stir at70° C. for an additional hour and then cooled to room temperature. Thereaction was then diluted with dichloromethane and saturated aqueoussodium bicarbonate. The solution was then further diluted with saturatedaqueous sodium thiosulfate. The layers were separated and the aqueouslayer was extracted two additional times with dichloromethane. Theorganic extracts were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The resulting residue was preadsorbed ontosilica gel and purified by silica gel flash chromatography (ethylacetate-heptane 0 to 50%) to provide5-bromo-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z266.2 (M+H)⁺.

d)4-Cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one

To a solution of 5-bromo-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one,(340 mg, 1.28 mmol), in DMSO (8. mL) was added bis(pinacolato)diboron(357 mg, 1.41 mmol), and potassium acetate (313 mg, 3.2 mmol). Next,[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) complexedwith dichloromethane (CAS#72287-26-4, 52 mg, 0.064 mmol) was added. Thereaction mixture was degassed by bubbling nitrogen through the solutionfor 3 minutes. The reaction was then heated at 80° C. for 16 hr. Thereaction was then cooled to room temperature, diluted with diethyl etherand filtered through Celite®. The filtrate was then diluted with waterand the layers were separated. The aqueous layer was extracted twoadditional times with diethyl ether. The organic extracts were combined,washed with brine, dried over anhydrous magnesium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-heptane, 0 to 70%) to afford4-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one;MS: (ES+) m/z 314.0 (M+H)⁺.

e)4-Cyclopropyl-5-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To4-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one,(50 mg, 0.160 mmol) was added (5-bromo-pyridin-3-yl)-methanol(CAS#37669-64-0, 36 mg, 0.192 mmol), 1,2-dimethoxyethane (1.0 mL), and 2M aqueous sodium carbonate (0.200 mL, 0.40 mmol). The reaction mixturewas degassed and placed under an argon atmosphere, at which time resinbound tetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (73 mg, 0.008 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 130° C. for 1 hours. Thereaction mixture was then cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was partially purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 10%). Further purification wasaccomplished via reverse phase HPLC (10 to 40% acetonitrile/water w/0.1%NH₄OH) to furnish4-Cyclopropyl-5-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 295.14485 (M+H)+; 1H NMR (400 MHz, CDCl₃) δ ppm0.17-0.25 (m, 2H), 0.72-0.80 (m, 2H), 1.87-1.98 (m, 1H), 3.25 (s, 3H),3.64 (s, 2H), 4.83 (s, 2H), 6.80 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.8 Hz,1H), 7.80 (t, J=2.0 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.61 (d, J=2.0 Hz,1H).

Example 415-(5-Bromo-pyridin-3-yl)-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one

To4-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one,prepared as described in Example 40d (50 mg, 0.16 mmol) was added3,5-dibromopyridine (CAS#625-92-3, 113 mg, 0.479 mmol),1,2-dimethoxyethane (1.5 mL), and 2 M aqueous sodium carbonate (0.2 mL,0.4 mmol). The reaction mixture was degassed and placed under an argonatmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (43.5 mg, 4.79 μmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 120° C. for 3 hours. Thereaction mixture was then cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography (ethylacetate-heptane, 10 to 75%) to furnish5-(5-bromo-pyridin-3-yl)-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 343.0451 (M+H)+; 1H NMR (400 MHz, CDCl₃) δ ppm 0.18-0.26(m, 2H), 0.78-0.88 (m, 2H), 1.87-1.99 (m, 1H), 3.25 (s, 3H), 3.64 (s,2H), 6.82 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 8.62(d, J=1.4 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H).

Example 42 4-Cyclopropyl-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one

To 5-bromo-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one, prepared asdescribed in Example 40c, (320 mg, 1.202 mmol), was added 3-pyridineboronic acid (CAS#1692-25-7, 177 mg, 1.443 mmol), 1,2-dimethoxyethane(7.5 mL), and 2 M aqueous sodium carbonate (1.503 ml, 3.01 mmol). Thereaction mixture was degassed and placed under an argon atmosphere, atwhich time resin bound tetrakis(triphenylphosphine)palladium(0),specifically polystyrene triphenylphosphine palladium (0) [PS—PPh₃-Pd(0)(Biotage), 0.11 mmol/g loading, (328 mg, 0.036 mmol)] was added. Thereaction vessel was sealed and was heated by microwave irradiation at130° C. for 4 hours. The reaction mixture was then cooled to roomtemperature, diluted with dichloromethane and filtered through glasswool. The filtrate was further diluted with saturated aqueous sodiumbicarbonate and the layers were separated. The aqueous layer wasextracted two times with dichloromethane, and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-heptane, 10 to 100%) to furnish4-cyclopropyl-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS:(ESI) m/z 265.1342 (M+H)+; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 0.12-0.24 (m,2H), 0.68-0.78 (m, 2H), 1.86-2.00 (m, 1H), 3.19 (s, 3H), 3.59 (s, 2H),6.80 (d, J=7.8 Hz, I H), 7.21 (d, J=8.1 Hz, 1H), 7.34 (dd, J=7.7, 4.9Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 8.53 (d, J=4.6 Hz, 1H), 8.63 (s, 1H).

Example 43 a) (3-Bromo-5-chloro-pyridin-4-yl)-methanol

To a solution of diisopropylamine (0.963 ml, 6.76 mmol) in THF (45 ml)at −78° C. was added n-butyllithium (2.5M in hexanes, 2.5 mL, 6.24mmol). The reaction mixture was stirred for 15 minutes, at which time3-bromo-5-chloropyridine (CAS#73583-39-8, 1.0 g, 5.20 mmol) in THF (10.0mL) was added followed by a 1.5 mL THF wash. After 10 minutes methylchloroformate (0.443 ml. 5.72 mmol) was added. The reaction was stirredfor 20 minutes and then quenched at −78° C. with 5% AcOH in MeOH. Thereaction was then diluted with saturated aqueous ammonium chloride andplaced at room temperature. The reaction was then diluted with DCM andsaturated aqueous sodium bicarbonate and the layers were separated. Theaqueous layer was extracted two times with dichloromethane, and theorganic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The resulting ester was used without furtherpurification. To a solution of lithium aluminum hydride (109 mg, 2.87mmol) in THF (30 ml) at −78° C. was added a solution of the esterprepared above (450 mg, 1.797 mmol) in THF (7.0 mL). The reaction waspermitted to warm to −30° C. and stirred for 45 minutes. The reactionwas then quenched with 0.9 mL of a 9:1 THF/H2O solution followed by 2 NNaOH (0.3 mL). The reaction was placed at rt and water (1.0 mL) wasadded followed by THF (9 mL). The reaction was stirred for 5 minutes andthen charged with magnesium sulfate (ca. 1.0 g). The resulting mixturewas filtered through a pad of Celite® and the filtrate was concentrated.The resulting residue was purified by silica gel flash chromatography(ethanol-dichloromethane, 0 to 7%) to afford(3-bromo-5-chloro-pyridin-4-yl)-methanol; ¹H NMR (400 MHz, CDCl₃) δ ppm4.94 (s, 2H), 8.52 (s, 1H), 8.62 (s, 1H).

b)4-Chloro-5-(5-chloro-4-hydroxymethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one

To4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one,prepared as described in Example 27a (80 mg, 0.260 mmol) was added(3-bromo-5-chloro-pyridin-4-yl)-methanol (69.4 mg, 0.312 mmol)1,2-dimethoxyethane (3 mL), and 2 M aqueous sodium carbonate (0.325 ml,0.650 mmol). The reaction mixture was degassed and placed under an argonatmosphere, at which time resin boundtetrakis(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (118 mg, 0.013 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 120° C. for 2 hours. Thereaction mixture was then cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was semi-purified by silica gel flash chromatography(ethanol-dichloromethane, 10 to 100%). The resulting residue waspurified by semi-preparative reverse phase HPLC (10 to 45%acetonitrile/water w/0.1% NH₄OH) to afford4-chloro-5-(5-chloro-hydroxymethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one;HRMS: (ESI) m/z 323.0358 (M+H)+; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.28 (s,3H), 3.62 (s, 2H), 4.48 (d, J=12.3 Hz, 1H), 4.76 (d, J=12.4 Hz, 1H),6.87 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 8.41 (s, 1H), 8.69 (s,1H).

Example 44 a) 4-Benzyloxy-1-methyl-1H-indole

To a solution of 4-benzyloxy-1H-indole (CAS#20289-26-3, 10.85 g, 48.6mmol) in N,N-dimethylformamide (200 mL) at 0° C., was added sodiumhydride (60% dispersion in oil, 2.24 g, 55.9 mmol). The reaction waspermitted to stir for 15 minutes at 0° C. Then Iodomethane (3.19 mL,51.0 mmol) was added to the reaction mixture. The reaction was put atroom temperature and permitted to stir 30 minutes. The reaction was thenquenched with saturated aqueous ammonium chloride. The mixture wasdiluted with water and extracted with diethyl ether. The layers wereseparated and the aqueous layer was then extracted two additional timeswith diethyl ether. The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated to afford4-benzyloxy-1-methyl-1H-indole; MS: (ES+) m/z 238.4 (M+H)⁺.

b) 4-Benzyloxy-5-bromo-1-methyl-1,3-dihydro-indol-2-one

To a solution of potassium bromide (3.08 g, 25.8 mmol) in water (50 mL)was added bromine (0.667, 12.92 mmol). A separate flask containing4-benzyloxy-1-methyl-1H-indole (1.46 g, 6.15 mmol) was charged withtert-butanol (50 ml). The mixture was heated to 50° C. untilhomogeneous. Then water (50 mL) was added to the solution. The mixturewas cooled to −10° C. and 50 mL of the bromine solution prepared abovewas added dropwise over 1 hour. During the addition, the temperature wasmaintained at −10° C. After addition was complete, the reaction wasneutralized with saturated aqueous sodium bicarbonate and quenched withsaturated aqueous sodium thiosulfate. The reaction mixture was thendiluted with dichloromethane and saturated aqueous sodium bicarbonateand the layers were separated. The aqueous layer was extracted twoadditional times with dichloromethane and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated. The resulting residue was dissolved in acetic acid (20 mL)and zinc dust (1.58 g, 24.33 mmol) was added. The reaction was permittedto stir for 30 minutes at room temperature. Then the reaction mixturewas then diluted with dichloromethane (100 mL) and filtered. To thefiltrate, ice-water was added, followed by solid sodium carbonate untilthe pH of reaction mixture to was ca. 8. The resulting layers wereseparated and the aqueous layer was extracted two additional times withdichloromethane. The organic layers were combined, dried over anhydroussodium sulfate, filtered, and concentrated. The resulting residue waspurified by silica gel flash chromatography (ethyl acetate-heptane, 0 to60%) to afford 4-benzyloxy-5-bromo-1-methyl-1,3-dihydro-indol-2-one. MS:(ES+) m/z 332.0 (M+H)⁺.

c) 4-Benzyloxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one

To 4-benzyloxy-5-bromo-1-methyl-1,3-dihydro-indol-2-one (100 mg, 0.301mmol) was added 3-pyridineboronic acid (CAS#1692-25-7, 44.4 mg, 0.361mmol), 1,2-dimethoxyethane (2 mL) and 2 M aqueous sodium carbonate(0.376 ml, 0.753 mmol). The reaction mixture was degassed and placedunder an argon atmosphere, at which time resin boundtetrads(triphenylphosphine)palladium(0), specifically polystyrenetriphenylphosphine palladium (0) [PS—PPh₃-Pd(0) (Biotage), 0.11 mmol/gloading, (82 mg, 0.0093 mmol)] was added. The reaction vessel was sealedand was heated by microwave irradiation at 130° C. for 2.5 hours. Thereaction mixture was cooled to room temperature, diluted withdichloromethane and filtered through glass wool. The filtrate wasfurther diluted with saturated aqueous sodium bicarbonate and the layerswere separated. The aqueous layer was extracted two times withdichloromethane, and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel flash chromatography (ethylacetate-dichloromethane, 0 to 100%) to afford4-benzyloxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI)m/z 331.1447 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.16 (s, 3H), 3.77(s, 2H), 4.93 (s, 2H), 6.88 (d, J=8.08 Hz, 1H), 7.16-7.21 (m, 2H),7.27-7.31 (m, 3H), 7.35 (d, J=8.08 Hz, 1H), 7.41 (qd, 1H), 7.86 (dt,J=7.83, 2.02 Hz, 1H), 8.52 (dd, J=4.80, 1.77 Hz, 1H), 8.67 (dd, J=2.27,0.76 Hz, 1H).

Example 45 a) 4-Hydroxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one

To a solution of4-benzyloxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one (0.3 g,0.908 mmol) in ethanol (20 mL), was added 10% palladium on carbon (0.2g, 0.28 mmol). The atmosphere over the reaction mixture was evacuatedand the reaction was placed under an atmosphere of hydrogen gas via aballoon. The reaction was permitted to stir for 1 hour. The reactionmixture was then filtered through a plug of Celite®. The Celite pad waswashed with hot ethanol (200 ml). The combined filtrate was thenconcentrated to afford4-hydroxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; MS: (ES+) m/z241.1 (M+H)⁺.

b) 4-Ethoxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one

A microwavable vial was charged with4-hydroxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one (48.1 mg, 0.2mmol), toluene (2 ml), and ethanol (23.3 L, 0.4 mmol).Cyanomethylene-tri-n-butylphosphorane (CAS#157141-27-0, 169 mg, 0.700mmol) was then added to the vial. The reaction vial was sealed and washeated by microwave irradiation at 105° C. for 1 hour. The reactionmixture was cooled to room temperature and diluted with dichloromethaneand brine. The layers were separated and the aqueous layer was extractedan additional two times with dichloromethane. The organic layers werecombined, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-heptane, 0 to 100%). Further purificationwas accomplished via reverse phase HPLC (10 to 40% acetonitrile/waterw/0.1% NH₄OH) to afford4-ethoxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI)m/z 269.1289 (M+H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 1.16 (t, J=6.95 Hz,3H), 3.20 (s, 3H), 3.60 (s, 2H), 3.85 (q, J=6.91 Hz, 2H), 6.68 (d,J=8.08 Hz, 1H), 7.28 (d, J=8.08 Hz, 1H), 7.32 (dd, J=7.83, 4.80 Hz, 1H),7.85 (dt, J=7.89, 1.99 Hz, 1H), 8.51 (dd, J=4.80, 1.77 Hz, 1H), 8.71 (d,J=2.78 Hz, 1H).

Example 46 a) 3-Bromo-5-oxiranyl-pyridine

To a solution of trimethylsulfoxonium iodide (CAS#1774-47-6, 11.83 g,53.8 mmol) in methyl sulfoxide (80 mL), was added slowly sodium hydride(60% dispersion in oil, 1.989 g, 49.7 mmol). The reaction was permittedto stir for 15 min at room temperature. A solution of5-bromo-pyridine-3-carbaldehyde (CAS#135124-70-8, 5.0 g, 26.9 mmol) indimethylsulfoxide (20 mL) was added slowly to the reaction mixture. Thereaction permitted to stir for 10 minutes after the addition wascomplete. The reaction was cooled to 0° C., quenched with brine, anddiluted with diethyl ether. The layers were separated and the aqueouslayer was extracted two additional times with diethyl ether. The organiclayers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-heptane, 0 to 60%) to afford3-bromo-5-oxiranyl-pyridine; MS: (ES+) m/z 200.0 (M+H)⁺.

b) 3-Bromo-5-oxetan-2-yl-pyridine

To a suspension of trimethylsulfoxonium iodide (CAS#1774-47-6, 6.38 g,29.0 mmol) in tert-butanol (20 mL), was added potassium tert-butoxide(3.25 g, 29.0 mmol). The reaction was heated to 50° C. and permitted tostir for 15 min. A solution of 3-bromo-5-oxiranyl-pyridine (2.9 g, 14.50mmol) in tert-butanol (20 mL) was then added slowly to the reaction. Thereaction was permitted to stir at 50° C. for 16 hr. The reaction mixturewas cooled to 0° C., quenched with brine, and diluted with diethylether. The layers were separated and the aqueous layer was extractedwith diethyl ether two additional times. The organic layers werecombined, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gel flashchromatography (ethyl acetate-heptane, 0 to 60%) to afford3-bromo-5-oxetan-2-yl-pyridine; MS: (ES+) m/z 214.3 (M+H)⁺.

c) (R)- and(S)-1-methyl-5-(5-oxetan-2-yl-pyridin-3-yl)-1,3-dihydro-indol-2-one

The above compounds was prepared in a similar fashion as described inExample 4; HRMS: (ESI) m/z 281.1295 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δppm 2.65-2.78 (m, 1H), 3.17-3.27 (m, 1H), 3.29 (s, 3H), 3.64 (s, 2H),4.66-4.82 (m, 1H), 4.88-5.05 (m, 1H), 6.00 (t, J=7.52 Hz, 1H), 6.99 (d,J=8.08 Hz, 1H), 7.44-7.68 (m, 2H), 8.31 (br. s., 1H), 8.64 (d, J=1.64Hz, 1H), 8.81 (d, J=2.02 Hz, 1H). Resolution of the enantiomers of thetitle compound was achieved via chiral chromatography by using aChiralPak IA column with 70/30 isopropanol/heptane as mobile phase toprovide (R)- or(S)-1-methyl-5-(5-oxetan-2-yl-pyridin-3-yl)-1,3-dihydro-indol-2-one(t_(r)=23.5 min) and (R)- or(S)-1-methyl-5-(5-oxetan-2-yl-pyridin-3-yl)-1,3-dihydro-indol-2-one(t_(r)=35.4 min).

By repeating the procedures described in the examples above, usingappropriate starting materials, the following compounds of Formula I, asidentified in Table 2, were obtained.

Example 47 1,3-Dimethyl-5-pyridin-3-yl-1,3-dihydro-benzoimidazol-2-one

a)-Bromo-1,3-dimethyl-1,3-dihydro-4-benzoimidazol-2-one

Sodium hydride (60% in mineral oil, 256 mg, 6.4 mmol) was added to asolution of 5-Bromo-1,3-dihydro-1,3-dihydro-benzoimidazol-2-one (427 mg,2 mmol) in DMF (20 mL) at room temperature. After 10 min, iodomethane(710 mg, 5 mmol) was added dropwise, and the resulting mixture wasstirred at room temperature for overnight (15 hrs). The reaction wasquenched with water (100 mL) and extracted with ethyl acetate (125mL×3). The combined extracts were washed with water (100 mL×2),saturated aqueous NaCl solution (100 mL), dried with MgSO₄. Afterconcentration, a pale yellow solid was obtained (539 mg) without furtherpurification.

b) 1,3-Dimethyl-5-pyridin-3-yl-1,3-dihydro-benzoimidazol-2-one

A mixture of 5-Bromo-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (121mg, 0.5 mmol), 3-pyridyl boronic acid (68 mg, 0.55 mmol),polymer-supported Pd(PPh₃)₄ (0.09 mmol/g, 278 mg, 0.025 mmol) and Na₂CO₃(2 M in water, 0.55 mL., 1.1 mmol) in DME (3.3 mL) was heated to refluxfor 1 hr. After filtration and concentration, the residue was purifiedby flash column (MeOH—CH2Cl2, v/v, 0-7.5%) and yielded the titlecompound (38 mg). MS (ESI)/z 240.0 (M+H), retention time 1.00 min. ¹HNMR (400 MHz, CD₂Cl₂) δ ppm 3.47 (s, 3H), 3.49 (s, 3H), 7.13 (d, J=8.1Hz, 1H), 7.25 (s, 1H), 7.38-7.40 (m, 1H), 7.41-7.44 (m, 1H). 7.95-7.98(m, 1H), 8.60 (m, 1H), 8.90 (s, 1H).

Example 48 3-Methyl-6-pyridin-3-yl-3H-benzooxazol-2-one

a) 3-Methyl-3H-benzooxazol-2-one

A suspension of o-aminophenol (1.5 g, 13.7 mmol), K₂CO₃ (3.79 g, 27.4mmol) in dimethyl carbonate (96.3 g, 90 mL, 1069 mmol) was heated to 90°C. for 1 week. After filtration and concentration, a brownish solid (2g) was obtained without further purification. ¹H NMR (400 MHz, CD₂Cl₂) δppm 3.42 (s, 3H), 7.03 (m, 1H), 7.15-7.19 (m, 1H), 7.24-7.27 (m, 2H).

b) 6-Bromo-3-ethyl-3H-benzooxazol-2-one

A mixture of 3-Methyl-3H-benzooxazol-2-one (449 mg, 3 mmol), NBS (561mg, 3.15 mmol), AIBN (10 mg, catalytic amount, 0.061 mmol) in CCl₄ (20mL) was refluxed for 48 hrs. After filtration, the filtrates werediluted with ethyl acetate and washed with water. The organic layer wasdried over MgSO₄, filtered and concentrated to a reddish brown solid(667 mg) without further purification.

c) 3-Methyl-6-pyridin-3-yl-3H-benzooxazol-2-one

A suspension of 6-Bromo-3-methyl-3H-benzooxazol-2-one (115 mg, 0.5mmol), 3-pyridyl boronic acid (68 mg, 0.55 mmol), polymer-supportedPd(PPh₃)₄ (0.09 mmol/g, 278 mg, 0.025 mmol) and Na₂CO₃ (2 M in water,0.55 mL, 1.1 mmol) in DME (3.3 mL) was heated to reflux for 1.5 hr.After filtration and concentration, the residue was purified by flashcolumn (MeOH—CH₂Cl₂, v/v, 0-7%) and yielded the title compound (60 mg).MS (ESI) m/z 227.0 (M+H), retention time 1.04 min. ¹H NMR (400 MHz,CD₂Cl₂) δ ppm 3.47 (s, 3H), 7.15 (d, J=8.6 Hz, 1H), 7.41-7.44 (m, 1H),7.49 (s. 1H), 7.50 (d, J=7 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 8.61 (s,1H), 8.87 (s, 1H).

Example 49 3-Methyl-6-pyridin-3-yl-3H-benzothiazol-2-one

a) 6-Bromo-3-methyl-3H-benzothiazol-2-one

iodomethane (543 uL, 1.234 g, 8.7 mmol) was added dropwise to asuspension of 6-Bromo-3-hydro-3H-benzothiazol-2-one (1 g, 4.35 mmol),K₂CO₃ (1.5 g, 10.9 mmol) in DMSO (15 mL) at room temperature. Theresulting mixture was stirred for overnight. Water (20 mL) and ethylacetate (25 mL×3) were added, and the organic layer was separated,washed with brine and dried over anhydrous Na₂SO₄. After filtration andconcentration, a colorless solid was obtained (1.4 g). ¹H NMR (400 MHz,CDCl₃) δ ppm 3.42 (s, 3H), 6.89 (d, J=8.5 Hz, 1H), 7.43 (dd, J=2, 8.5Hz, 1H), 7.54 (d, J=2 Hz, 1H).

b) 3-Methyl-6-pyridin-3-yl-3H-benzothiazol-2-one

A suspension of 6-Bromo-3-methyl-3H-benzothiazol-2-one (200 mg, 0.82mmol), 3-pyridyl boronic acid (78 mg, 0.63 mmol), polymer-supportedPd(PPh₃)₄ (0.11 mmol/g, 115 mg, 0.0126 mmol) and Na₂CO₃ (2 M in water,0.65 mL, 1.3 mmol) in DME (7 mL) was heated to reflux for overnight.After filtration and concentration, the residue was purified by flashcolumn (MeOH—CH₂Cl₂, v/v, 0-4%) and yielded the title compound (200 mg).MS (ESI) m/z 243.0 (M+H. ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.52 (s, 3H),7.23 (d, J=8.4 Hz, 1H), 7.43-7.46 (m, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.73(s, 1H), 7.93-7.96 (m, 1H), 8.62 (m, 1H), 8.88 (s, 1H).

Example 50 6-(5-aminopyridin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one

a)3-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzothiazol-2-one

A mixture of 6-Bromo-3-methyl-3H-benzothiazol-2-one (1220.5 mg, 5 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1396.7 mg,5.5 mmol), PdCl2(dppf).CH2Cl2 (183 mg, 0.25 mmol), potassium acetate(980 mg, 10 mmol) in 1,4-dioxane (15 mL) was heated to 80° C. for 5 hrs.After concentration, the residue was purified by flash column (ethylacetate I heptane, v/v, 10-30%) and yielded the title compound (1.3 g).MS (ESI) m/z 292.0 (M+H)⁺.

b) Synthesis of6-(5-aminopyridin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one

A mixture of3-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzothiazol-2-one(873.5 mg, 3 mmol), 5-Bromo-pyridin-3-ylamine (519 mg, 3 mmol),Pd₂(dba)₃ (24.7 mg, 0.06 mmol), S—PHOS (62 mg, 0.15 mmol), K₃PO₄ (1.27g, 6 mmol) in toluene (15 mL) was heated to 95° C. for overnight. Afterfilteration, concentration, the residue was purified by flash column(MeOH/CH₂Cl₂, v/v, 1.5-3%) and yielded yellow solid (380 mg). MS (ESI)m/z 258.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.49 (s, 3H), 3.78 (brs,2H), 7.10-7.12 (m, 1H), 7.12 (s, 1H), 7.51 (dd, J=8, 2 Hz, 1H), 7.60 (d,J=2 Hz, 1H), 8.08 (d, J=2.6 Hz, 1H), 8.23 (d, J=2 Hz, 1H).

Example 51N-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)pyridin-3-yl)ethanesulfonamide

General sulfonylation procedure: EtSO₂Cl (51.4 mg, 0.4 mmol) was addeddropwise to a solution of6-(5-aminopyridin-3-yl)-3-methylbenzo[d]thiazol-2(3H)-one (Example 50:28 mg, 0.1 mmol) in pyridine (2 mL) at 0° C. The resulting mixture wasslowly warmed up to room temperature and stirred for additional 3 hrs atthis temperature. After concentration, the residue was purified by flashcolumn (MeOH/CH2Cl2, v/v, 1-3%) and yielded yellow solid (20 mg). MS(ESI) m/z 350.4 (M+H)⁺. ¹H NMR (400 MHz, MeOD) δ ppm 1.35 (t, J=7.4 Hz,3H), 3.22 (q, J=7.4 Hz, 2H), 3.51 (s, 3H), 7.38 (d, J=8 Hz, 1H), 7.68(d, J=8 Hz, 1H), 7.87 (s, 1H), 7.95 (s, 1H), 8.40 (s, 1H), 8.58 (s, 1H).

Example 52N-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)pyridin-3-yl)cyclopropanesulfonamide

The entitled compound was prepared as in Example 51 using the generalsulfonylation procedure. MS (ESI) m/z 360.0 (M+H)⁺ retention time 1.00min. ¹H NMR (400 MHz, CD₂Cl₂) δ ppm. 0.97-1.17 (m, 4H), 2.47 (m, 1H),3.44 (s, 3H), 6.52 (brs, 1H), 7.08 (d, J=8 Hz, 1H), 7.48 (d, J=8 Hz,1H), 7.58 (s, 1H), 7.84 (s, 1H), 8.37 (s, 1H), 8.59 (s, 1H).

TABLE 2 Compound # (Prepared According to Example #) Structure and NameNMR and/or ESMS 1a (Example 1)

HRM (ESI) m/z 303.0812 (M + H)⁺; 1H NMR (400 MHz, CDCl₃) δ ppm 3.18 (s,3 H), 3.29 (s, 3 H), 3.64 (s, 2 H), 6.98 (d, J = 8.1 Hz, 1 H), 7.49-7.63(m, 2 H), 8.41 (t, J = 2.2 Hz, 1 H), 9.09 (d, J = 2.3 Hz, 1 H), 9.10 (d,J = 2.3 Hz, 1 H). 1b (Example 1)

HRMS: (ESI) m/z 239.1818 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 2.31(s, 3 H), 3.22 (s, 3 H), 3.55 (s, 2 H), 6.92 (d, J = 8.1 Hz, 1 H),7.09-7.35 (m, 3 H), 8.29-8.49 (m, 2 H). 2a (Example 2)

MS: (ES+) m/z 225 (M + H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.18 (s, 3H), 3.64 (s, 2 H), 7.12 (d, J = 8.8 Hz, 1 H), 7.47 (ddd, J = 8.0, 4.8,0.8 Hz, 1 H), 7.65- 7.69 (m, 2 H), 8.05 (ddd, J = 7.9, 2.5, 1.7 Hz, 1H), 8.53 (dd, J = 4.7, 1.6 Hz, 1 H), 8.87 (d, J = 1.6 Hz, 1 H). 2b(Example 2)

MS: (ES+) m/z 255 (M + H); ¹H NMR (400 MHz, DMSO-d₆) of thetrifluoroacetic acid salt: δ ppm 3.18 (s, 3 H), 3.65 (s, 2 H), 3.95 (s,3 H), 7.13 (d, J = 8.9 Hz, 1 H), 7.73 (s, 1 H), 7.74-7.77 (m, 2 H), 8.33(d, J = 2.7 Hz, 1 H), 8.55 (d, J = 1.8 Hz, 1 H). 3c (Example 3)

HRMS: (ESI) m/z 240.1139 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.16(s, 3 H), 3.62 (s, 2 H), 5.36 (s, 2 H), 7.07 (d, J = 8.3 Hz, 1 H), 7.11(t, J = 2.3 Hz, 1 H), 7.48-7.57 (m, 2 H), 7.89 (d, J = 2.5 Hz, 1 H),8.00 (d, J = 2.0 Hz, 1 H). 3d (Example 3)

HRMS: (ESI) m/z 293.0904 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.28(s, 3 H), 3.60 (s, 2 H), 6.91 (d, J = 7.8 Hz, 1 H), 7.17-7.33 (m, 2 H),7.64 (d, J = 5.3 Hz, 1 H), 8.66 (s, 1 H), 8.79 (d, J = 5.1 Hz, 1 H). 3e(Example 3)

HRMS: (ESI) m/z 296.1401 (M + H)+; ¹H NMR (400 MHz, CDCl₃)  

 ppm 3.08 (br. s., 3 H), 3.18 (br. s., 3 H), 3.27 (s, 3 H), 3.62 (s, 2H), 6.95 (d, J = 8.1 Hz, 1 H), 7.43-7.58 (m, 2 H), 7.95 (t, J = 2.0 Hz,1 H), 8.63 (d, J = 1.8 Hz, 1 H), 8.86 (d, J = 2.3 Hz, 1 H). 3f (Example3)

HRMS: (ESI) m/z 310.1560 (M + H)+; ¹H NMR (400 MHz, DMSO-d₆)  

 ppm 1.21 (d, J = 6.57 Hz, 6 H), 3.18 (s, 3 H), 3.65 (s, 2 H), 4.06-4.22(m, 1 H), 7.14 (d, J = 8.8 Hz, 0 H), 7.70-7.80 (m, 2 H), 8.39 (d, J =4.3 Hz, 1 H), 8.50 (d, J = 7.8 Hz, 1 H), 8.92 (d, J = 2.0 Hz, 1 H), 8.98(d, J = 2.3 Hz, 1 H). 3g (Example 3)

HRMS: (ESI) m/z 374.1175 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm3.07-3.15 (m, 4 H), 3.29 (s, 3 H), 3.65 (s, 2 H), 3.75- 3.84 (m, 4 H),6.98 (d, J = 8.1 Hz, 1 H), 7.53 (s, 1 H), 7.56 (d, J = 8.1 Hz, 1 H),8.21 (s, 1 H), 8.92 (d, J = 1.8 Hz, 1 H), 9.05 (d, J = 1.5 Hz, 1 H). 3h(Example 3)

HRMS: (ESI) m/z 332.1066 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.72(s, 6 H), 3.18 (s, 3 H), 3.64 (s, 2 H), 7.14 (d, J = 8.8 Hz, 1 H),7.71-7.92 (m, 2 H), 8.25 (t, J = 2.1 Hz, 1 H), 8.85 (d, J = 2.0 Hz, 1H), 9.19 (d, J = 2.0 Hz, 1 H). 3i (Example 3)

HRMS: (ESI) m/z 360.1381 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09(t, J = 7.2 Hz, 6 H), 3.18 (s, 3 H), 3.26 (q, J = 7.1 Hz, 4 H), 3.65 (s,2 H), 7.14 (d, J = 8.8 Hz, 1 H), 7.73-7.82 (m, 2 H), 8.31 (t, J = 2.1Hz, 1 H), 8.90 (d, J = 2.0 Hz, 1 H), 9.14 (d, J = 2.3 Hz, 1 H). 4a(Example 4)

HRMS: (ESI) m/z 293.1037 (M + H)+; ¹H NMR (400 MHz, CDCl₃)  

 ppm 3.29 (s, 3 H), 3.65 (s, 2 H), 6.98 (d, J = 8.1 Hz, 1 H), 7.48-7.68(m, 2 H), 8.43-8.68 (m, 2 H), 9.01 (s, 1 H), 9.24 (s, 1 H). 4b (Example4)

HRMS: (ESI) m/z 255.1134 (M + H)+; ¹H NMR (400 MHz, DMSO-d₆)  

 ppm 3.15 (s, 3 H), 3.62 (s, 2 H), 4.59 (d, J = 5.6 Hz, 2 H), 5.39 (t, J= 5.8 Hz, 1 H), 7.10 (d, J = 8.8 Hz, 1 H), 7.64 (s, 1 H), 7.65 (s, 1 H),7.94 (t, J = 2.2 Hz, 1 H), 8.46 (d, J = 2.0 Hz, 1 H), 8.73 (d, J = 2.3Hz, 1 H). 4c (Example 4)

HRMS: (ESI) m/z 255.1130 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.16(s, 3 H), 3.61 (s, 2 H), 4.47 (d, J = 5.6 Hz, 2 H), 5.39 (t, J = 5.4 Hz,1 H), 7.07 (d, J = 8.6 Hz, 1 H), 7.23-7.36 (m, 2 H), 7.57 (d, J = 5.1Hz, 1 H), 8.36 (s, 1 H), 8.54 (d, J = 5.1 Hz, 1H). 4d (Example 4)

HRMS: (ESI) m/z 301.1340 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.29(s, 3 H), 3.64 (s, 2 H), 6.97 (d, J = 8.1 Hz, 1 H), 7.44-7.62 (m, 5 H),7.62-7.73 (m, 2 H), 8.10 (s, 1 H), 8.73-8.87 (m, 2 H). 4e (Example 4)

HRMS: (ESI) m/z 241.0976 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆)  

 ppm 3.15 (s, 3 H), 3.61 (s, 2 H), 7.08 (d, J = 8.1 Hz, 1 H), 7.27-7.39(m, 1 H), 7.51- 7.73 (m, 2 H), 8.08 (d, J = 2.8 Hz, 1 H), 8.31 (d, J =2.0 Hz, 1 H), 9.97 (s, 1 H). 5a (Example 5)

MS: (ES+) m/z 293 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆ δ ppm 3.16 (s, 3H), 3.62 (s, 2 H), 7.11 (d, J = 8.7 Hz, 1 H), 7.75-7.81 (m, 2 H), 8.39(s, 1 H), 8.87 (s, 1 H), 9.15 (s, 1 H). 5b (Example 5)

MS: (ES+) m/z 331 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.15 (s, 3H), 3.62 (s, 2 H), 5.29 (s, 2 H), 7.09 (d, J = 8.6 Hz, 1 H), 7.34 (d, J= 7.1 Hz, 1 H), 7.40 (t, J = 7.3 Hz, 2 H), 7.44-7.51 (m, 2 H), 7.69 (br.s., 2 H), 7.82 (s, 1 H), 8.35 (s, 1 H), 8.52 (s, 1 H). 5c (Example 5)

MS: (ES+) m/z 250 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.20 (s, 3H), 3.67 (s, 2 H), 7.20 (d, J = 8.0 Hz, 1 H), 7.59 (s, 1 H), 7.62 (d, J= 8.0 Hz, 1 H), 7.97 (dd, J = 5.1, 0.82 Hz, 1 H), 8.79 (d, J = 5.0 Hz, 1H), 8.89 (d, J = 0.8 Hz, 1 H). 5d (Example 5)

MS: (ES+) m/z 338 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.15 (s, 3H), 3.34 (s, 4 H), 3.59- 3.63 (m, 4 H), 7.09 (d, J = 8.7 Hz, 1 H),7.67-7.71 (m, 2 H), 8.04 (t, J = 2.1 Hz, 1 H), 8.52 (d, J = 1.9 Hz, 1H), 8.91 (d, J = 2.3 Hz, 1 H). 5e (Example 5)

MS: (ES+) m/z 250 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.18 (s, 3H), 3.65 (s, 2 H), 7.15 (d, J = 8.5 Hz, 1 H), 7.77-7.81 (m, 2 H), 8.63(t, J = 2.2 Hz, 1 H), 8.96 (d, J = 1.9 Hz, 1 H), 9.18 (d, J = 2.4 Hz, 1H). 5f (Example 5)

MS: (ES+) m/z 264 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.15 (s, 3H), 3.62 (s, 2 H), 4.13 (s, 2 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.61-7.68(m, 2 H), 8.00 (s, 1 H), 8.48 (s, 1 H), 8.80 (s, 1 H). 5g (Example 5)

MS: (ES+) m/z 259 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.18 (s, 3H), 3.64 (s, 2 H), 7.13 (d, J = 9.0 Hz, 1 H), 7.73-7.77 (m, 2 H), 8.22(t, J = 2.2 Hz, 1 H), 8.58 (d, J = 2.3 Hz, 1 H), 8.86 (d, J = 2.0 Hz, 1H). 6d (Example 6)

HRMS: (ESI) m/z 253.1340 (M + H)+; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.33(t, J = 7.6 Hz, 3 H), 2.74 (q, J = 7.6 Hz, 2 H), 3.27 (s, 3H) 3.61 (s, 2H), 6.93 (d, J = 8.1 Hz, 1 H), 7.41-7.57 (m, 2 H), 7.67 (s, 1 H), 8.44(s, 1 H), 8.65 (s, 1 H). 7c (Example 7)

HRMS: (ES+) m/z 332.1068 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00(t, J = 7.2 Hz, 3 H), 2.83-2.92 (m, 2 H), 3.18 (s, 3 H), 3.65 (s, 2 H),7.15 (d, J = 8.1 Hz, 1 H), 7.72-7.77 (m, 2 H), 7.80 (t, J = 5.6 Hz, 1H), 8.33 (t, J = 2.3 Hz, 1 H), 8.86 (d, J = 2.0 Hz, 1 H), 9.12 (d, J =2.3 Hz, 1 H). 16c (Example 16)

HRMS: (ESI) m/z 311.1768 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃)  

 ppm 0.84 (t, J = 7.45 Hz, 6 H), 1.85 (s, 1 H), 1.89-2.00 (m, 4 H), 3.28(s, 3 H), 3.63 (s, 2 H), 6.96 (d, J = 8.08 Hz, 1 H), 7.52 (s, 1 H), 7.55(d, J = 8.08 Hz, 1 H), 8.11 (s, 1 H), 8.62 (s, 1 H), 8.72 (s, 1 H). 19c(Example 19)

HRMS: (ES+) m/z 273.0796 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.36(s, 3 H), 3.28 (s, 3 H), 3.61 (s, 2 H), 6.93 (d, J = 8.1 Hz, 1 H),7.16-7.25 (m ,2 H), 8.33 (s, 1 H), 8.53 (s, 1 H) 23a (Example 23)

HRMS: (ESI) m/z 303.1246 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆)  

 3.18 (s, 3 H), 3.65 (s, 2 H), 7.15 (d, J = 8.59 Hz, 1 H), 7.78-7.87 (m,2 H), 8.49 (t, J = 2.15 Hz, 1 H), 8.97 (dd, J = 4.93, 2.15 Hz, 2 H),9.27 (s, 1 H), 9.34 (s, 2 H) 23b (Example 23)

HRMS: (ESI) m/z 259.0640 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.58(s, 3 H), 3.59 (s, 2 H), 7.39 (s, 1 H), 7.39-7.43 (m, 1 H), 7.47 (s, 1H), 7.88 (d, J = 8.1 Hz, 1 H), 8.57 (d, J = 6.3 Hz, 1 H), 8.80 (s, 1 H).26d (Example 26)

HRMS: (ESI) m/z 259.0640 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.17(s, 3 H), 3.61 (s, 2 H), 7.29 (s, 1 H), 7.36 (s, 1 H), 7.50 (m, 1 H),7.85 (m, 1 H), 8.56-8.63 (m, 2 H) 26e (Example 26)

HRMS: (ESI) m/z 293.0251 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.27(s, 3 H), 3.61 (s, 2 H), 6.85 (d, J = 8.1 Hz, 1 H), 7.30 (d, J = 8.1 Hz,1 H), 7.78 (t, J = 2.0 Hz, 1 H), 8.56 (d, J = 1.77 Hz, 1 H), 8.60 (d, J= 2.3 Hz, 1 H) 26f (Example 26)

HRMS: (ESI) m/z 273.0796 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.22(s, 3 H), 3.28 (s, 3 H), 3.61 (s, 2 H), 6.84 (d, J = 8.1 Hz, 1H) 7.18(d, J = 8.1 Hz, 1 H), 7.31 (d, J = 5.1 Hz, 1 H), 8.38 (s, 1 H), 8.53 (d,J = 5.1 Hz, 1 H). 26g (Example 26)

HRMS: (ESI) m/z 273.0801 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.45(s, 3 H), 3.27 (s, 3 H), 3.61 (s, 2 H), 6.84 (d, J = 8.1 Hz, 1H) 7.29(d, J = 8.1 Hz, 1 H), 7.66 (br. s., 1 H), 8.47 (s, 1 H), 8.49 (s, 1 H).27c (Example 27)

HRMS: (ESI) m/z 366.0692 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.83(s, 6 H), 3.28 (s, 3 H), 3.63 (s, 2 H), 6.89 (d, J = 8.1 Hz, 1H) 7.34(d, J = 7.96 Hz, 1 H), 8.19 (t, J = 2.0 Hz, 1 H), 8.88 (d, J = 1.9 Hz, 1H), 9.00 (d, J = 1.9 Hz, 1 H). 27d (Examples 16a and 27)

HRMS: (ESI) m/z 317.1065 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51(s, 6 H), 3.18 (s, 3 H), 3.66 (s, 2 H), 5.27 (s, 1 H), 7.11 (d, J = 8.1Hz, 1 H), 7.42 (d, J = 8.1 Hz, 1 H), 7.88 (t, J = 2.2 Hz, 1 H), 8.46 (d,J = 2.3 Hz, 1 H), 8.70 (d, J = 2.0 Hz, 1 H). 27e (Example 27)

HRMS: (ESI) m/z 289.0753 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.17(s, 3 H), 3.66 (s, 2 H), 4.60 (d, J = 5.6 Hz, 2 H), 5.38 (t, J = 5.8 Hz,1 H), 7.11 (d, J = 8.1 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.76 (t, J =2.1 Hz, 1 H), 8.48 (d, J = 2.0 Hz, 1 H), 8.53 (d, J = 2.0 Hz, 1 H). 27f(Examples 10a and 27)

HRMS: (ESI) m/z 330.1376 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.24(t, J = 7.1 Hz, 6 H), 3.27 (s, 3 H), 3.44 (q, J = 7.1 Hz, 4 H), 3.62 (s,2 H), 6.86 (d, J = 8.0 Hz, 1 H), 7.21 (br. s., 1 H), 7.31 (d, J = 8.0Hz, 1 H), 7.92 (d, J = 1.5 Hz, 1 H), 8.02 (d, J = 2.9 Hz, 1 H). 27g(Examples 12a and 27)

HRMS: (ESI) m/z 394.0994 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.44(t, J = 7.4 Hz, 3 H), 2.88 (s, 3 H), 3.11 (q, J = 7.5 Hz, 2 H), 3.28 (s,3 H), 3.62 (s, 2 H), 4.50 (s, 2 H), 6.86 (d, J = 8.0 Hz, 1 H), 7.32 (d,J = 8.0 Hz, 1 H), 8.02 (br. s., 1 H), 8.58 (s, 1 H), 8.67 (s, 1 H). 27h(Examples 19a and 27)

HRMS: (ESI) m/z 307.0410 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.23(s, 3 H), 3.28 (s, 3 H), 3.61 (s, 2 H), 6.84 (d, J = 7.8 Hz, 1 H), 7.18(d, J = 7.8 Hz, 1 H), 8.26 (s, 1 H), 8.58 (s, 1 H). 27i (Example 27)

HRMS: (ESI) m/z 277.0547 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.27(s, 3 H), 3.62 (s, 2 H), 6.85 (d, J = 8.1 Hz, 1 H), 7.31 (d, J = 7.8 Hz,1 H), 7.46- 7.61 (m, 1 H), 8.46-8.55 (m, 2 H). 38a (Example 38)

HRMS: (ESI) m/z 289.0742 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) d ppm 3.15(s, 3 H), 3.81 (s, 3 H), 3.87 (s, 2 H), 6.83 (d, J = 8.1 Hz, 1 H), 7.38(d, J = 7.8 Hz, 1 H), 7.95-7.98 (m, 1 H), 8.57 (d, J = 2.3 Hz, 1 H),8.61 (d, J = 1.7 7Hz, 1 H). 38b (Example 38)

HRMS: (ESI) m/z 273.1035 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.14(s, 3 H), 3.80 (s, 3 H), 3.85 (s, 2 H), 6.83 (d, 1 H), 7.37 (d, J = 8.1Hz, 1 H), 7.78 (dt, J = 10.4, 2.8, 1.8 Hz, 1 H), 8.51 (d, J = 2.8 Hz, 1H), 8.53 (t, J = 1.8 Hz, 1 H). 38c (Examples 38 and 19a)

HRMS: (ESI) m/z 303.0899 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.16(s, 3 H), 3.15 (s, 3 H), 3.76 (s, 3 H), 3.89 (s, 2 H), 6.79 (d, J = 7.83Hz, 1 H), 7.14 (d, J = 7.83 Hz, 1 H), 8.24 (s, 1 H), 8.55 (s, 1 H). 39e(Example 39)

HRMS: (ESI) m/z 250.0978 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.63(s, 3 H), 3.65 (s, 2 H), 7.46 (dd, J = 8.0, 4.9 Hz, 1 H), 7.65 (d, J =1.5 Hz, 1 H), 7.70 (d, J = 1.8 Hz, 1 H), 7.82-7.94 (m, 1 H), 8.66 (dd, J= 4.9, 1.4 Hz, 1 H), 8.82 (d, J = 2.3 Hz, 1 H) 39f (Example 39)

HRMS: (ESI) m/z 250.0973 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.30(s, 3 H), 3.79 (s, 2 H), 7.13 (d, J = 8.1 Hz, 1 H), 7.48 (d, J = 8.1 Hz,1 H), 7.50- 7.54 (m, 1 H), 8.00 (d, J = 7.8 Hz, 1 H), 8.71 (d, J = 4.0Hz, 1 H), 8.78 (d, J = 1.5 Hz, 1 H). 40f (Example 40)

HRMS: (ESI) m/z 283.1246 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm0.16-0.24 (m, 2 H), 0.72-0.81 (m, 2 H), 1.86- 1.98 (m, 1 H), 3.20 (s, 3H), 3.59 (s, 2 H), 6.80 (d, J = 8.08 Hz, 1 H), 7.21 (d, J = 8.08 Hz, 1H), 7.44- 7.51 (m, 1 H), 8.41 (d, J = 2.78 Hz, 1 H), 8.47 (t, J = 1.64Hz, 1 H). 42a (Example 42)

HRMS: (ESI) m/z 299.0957 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm0.14-0.25 (m, 2 H), 0.74-0.83 (m, 2 H), 1.85- 2.00 (m, 1 H), 3.20 (s, 3H), 3.59 (s, 2 H), 6.81 (d, J = 7.83 Hz, 1 H), 7.21 (d, J = 7.83 Hz, 1H), 7.77 (t, J = 2.15 Hz, 1 H), 8.52 (d, J = 2.27 Hz, 1 H), 8.54 (d, J =2.02 Hz, 1 H) 45f (Example 45)

HRMS: (ESI) m/z 365.1055 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.20(s, 3 H), 3.52 (s, 2 H), 4.74 (s, 2 H), 6.73 (d, J = 8.08 Hz, 1 H), 7.06(d, J = 8.34 Hz, 2 H), 7.24 (d, J = 8.34 Hz, 2 H), 7.31 (d, J = 7.83 Hz,1 H), 7.39 (dd, J = 7.83, 5.05 Hz, 1 H), 7.92 (d, J = 7.83 Hz, 1 H),8.54 (d, J = 6.32 Hz, 1 H), 8.73 (s, 1 H). 45g (Example 45)

HRMS: (ESI) m/z 365.1058 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.20(s, 3 H), 3.52 (s, 2 H), 4.72 (s, 2 H), 6.73 (d, J = 8.08 Hz, 1 H), 7.02(d, J = 7.33 Hz, 1 H), 7.10 (s, 1 H), 7.18-7.34 (m, 4 H), 7.82 (d, J =7.83 Hz, 1 H), 8.53 (d, J = 4.55 Hz, 1 H), 8.70 (s, 1 H). 45h (Example45)

HRMS: (ESI) m/z 365.1055 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.20(s, 3 H), 3.52 (s, 2 H), 4.86 (s, 2 H), 6.73 (d, J = 8.08 Hz, 1 H),7.15-7.33 (m, 6 H), 7.85 (dt, J = 7.89, 1.99 Hz, 1 H), 8.52 (d, J = 6.06Hz, 1 H), 8.72 (d, J = 1.77 Hz, 1 H). 45i (Example 45)

HRMS: (ESI) m/z 337.1010 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.19(s, 3 H), 3.44 (s, 2 H), 4.86 (s, 2 H), 6.72 (d, J = 7.83 Hz, 1 H), 6.79(d, J = 3.03 Hz, 1 H), 6.90 (dd, J = 5.05, 3.54 Hz, 1 H), 7.27 (dd, J =5.18, 1.14 Hz, 1 H), 7.30 (d, J = 7.83 Hz, 1 H), 7.37 (dd, J = 7.58,5.31 Hz, 1 H), 7.91 (d, J = 7.83 Hz, 1 H), 8.54 (d, J = 4.29 Hz, 1 H),8.72 (s, 1 H). 45j (Example 45)

HRMS: (ESI) m/z 338.0959 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.20(s, 3 H), 3.55 (s, 2 H), 5.06 (s, 2 H), 6.74 (d, J = 7.83 Hz, 1 H),7.25-7.39 (m, 3 H), 7.68 (d, J = 3.28 Hz, 1 H), 7.87 (d, J = 7.83 Hz, 1H), 8.54 (br. s., 1 H), 8.73 (br. s., 1 H). 45k (Example 45)

HRMS: (ESI) m/z 356.1400 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.20(s, 3 H), 3.53 (s, 2 H), 4.81 (s, 2 H), 6.73 (d, J = 8.08 Hz, 1 H), 7.25(d, J = 8.59 Hz, 2 H), 7.27-7.33 (m, 2 H), 7.57 (d, J = 8.34 Hz, 2 H),7.80 (d, J = 8.34 Hz, 1 H), 8.52 (dd, J = 4.80, 1.52 Hz, 1 H), 8.71 (d,J = 1.52 Hz, 1 H). 45l (Example 45)

HRMS: (ESI) m/z 332.1396 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.16(s, 3 H), 3.79 (s, 2 H), 5.06 (s, 2 H), 6.88 (d, J = 7.83 Hz, 1 H),7.26-7.33 (m, 2 H), 7.35 (d, J = 8.08 Hz, 1 H), 7.40 (dd, J = 7.58, 4.55Hz, 1 H), 7.75 (td, J = 7.71, 1.77 Hz, 1 H), 7.89 (dt, J = 7.83, 2.02Hz, 1 H), 8.46-8.53 (m, 2 H), 8.67 (d, J = 2.27 Hz, 1 H). 45m (Example45)

HRMS: (ESI) m/z 361.1540 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.19(s, 3 H), 3.46 (s, 2 H), 3.77 (s, 3 H), 4.64 (s, 2 H), 6.70 (d, J = 8.08Hz, 1 H), 6.78 (d, J = 8.59 Hz, 2 H), 7.02 (d, J = 8.84 Hz, 2 H),7.24-7.36 (m, 2 H), 7.84 (dt, J = 7.83, 1.89 Hz, 1 H), 8.53 (d, J = 6.57Hz, 1 H), 8.72 (d, J = 1.52 Hz, 1 H). 45n (Example 45)

HRMS: (ESI) m/z 415.1268 (M + H)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ ppm 3.20(s, 3 H), 3.53 (s, 2 H), 4.74 (s, 2 H), 6.73 (d, J = 7.83 Hz, 1 H),7.04-7.22 (m, 4 H), 7.25-7.40 (m, 2 H), 7.80 (dt, J = 7.83, 1.89 Hz, 1H), 8.53 (d, J = 6.32 Hz, 1 H), 8.72 (s, 1 H). 45o (Example 45)

HRMS: (ESI) m/z 258.1319 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.14(s, 3 H), 3.84 (s, 2 H), 6.82 (d, J = 8.08 Hz, 1 H), 7.30 (d, J = 8.08Hz, 1 H), 7.43 (dd, J = 7.83, 4.80 Hz, 1 H), 7.84 (dt, J = 7.96, 2.02,1.89 Hz, 1 H), 8.51 (dd, J = 4.80, 1.77 Hz, 1 H), 8.63 (d, J = 3.03 Hz,1 H).

It can be seen that the compounds of the invention are useful asinhibitors of aldosterone Synthase activity and therefore useful in thetreatment of diseases and conditions mediated by Aldosterone synthasesuch as the metabolic disorders disclosed herein.

It will be understood that the invention has been described by way ofexample only and modifications may be made whilst remaining within thescope and spirit of the invention.

1. A compound of Formula I:

a pharmaceutically acceptable salt thereof, wherein: X is O, S or —NR¹;each R¹ are independently C₁₋₇alkyl or C₃₋₈cycloalkyl; each of R² and R⁶are independently hydrogen, halogen, cyano, C₁₋₇alkyl,hydroxy-C₁₋₇alkyl, —OR⁷, C₃₋₈cycloalkyl, halo-C₁₋₇alkyl or—CH₂—NR⁸—SO₂—R¹⁰; R³ and R⁴ are independently hydrogen, halogen orcyano; R⁵ is hydrogen, C₁₋₇alkyl, halogen, cyano, hydroxy,hydroxy-C₁₋₇alkyl, hydroxy-C₃₋₈cycloalkylalkyl, C₁₋₇alkoxy-C₃₋₈alkyl,—OR⁷, C₆₋₁₀aryl, heteroaryl, heterocyclyl, C₃₋₈cycloalkyl,halo-C₁₋₇alkyl, —NR⁸R⁹, —CH₂—NR⁸—C(O)NR⁸R⁹, —CH₂NR⁸—SO₂—R¹⁰, —C(O)—R¹⁰,—SO₂R¹⁰, —C(O)—NR⁸R⁹, —SO₂—NR⁸R⁹, —NR⁸C(O)—R¹⁰, —CH₂CN, or —NR⁸—SO₂R¹⁰;R⁷ is C₁₋₇alkyl, C₃₋₈cycloalkyl-C₁₋₇alkyl, heterocyclyl-C₁₋₇alkyl,C₆₋₁₀aryl-C₁₋₇alkyl, heteroaryl-C₁₋₇alkyl or —C(O)—R¹⁰; in whichC₆₋₁₀aryl, heteroaryl, C₁₋₇alkyl, heterocyclyl and C₃₋₈cycloalkyl areoptionally substituted with C₁₋₇alkoxy, halo, halo-C₃₋₈alkoxy,C₁₋₇alkyl, OH or halo-C₁₋₇alkyl; each of R⁸, R⁹ are independentlyhydrogen, C₁₋₇alkyl, halo-C₁₋₇alkyl, C₆₋₁₀aryl-C₁₋₇alkyl orheterocyclyl; or R⁸ and R⁹ can form together with the nitrogen atom towhich they are attached a 5- or 6-membered ring heterocyclyl, whereinsaid heterocyclyl optionally contain an additional heteroatom selectedfrom N, O or S and is optionally substituted with C₁₋₇alkyl; and R¹⁰ ishydrogen, C₁₋₇alkyl, halo-C₁₋₇alkyl, C₆₋₁₀aryl-C₁₋₇ alyl, —NR⁸R⁹, orheterocyclyl; wherein each heteroaryl is a mono- or bicyclic aromaticmoiety comprising 5-10 ring atoms selected from carbon atoms and 1 to 5heteroatoms, and each heterocyclyl is a mono- or bicyclic saturated orpartialy saturated but non-aromatic moiety comprising 4-10 ring atomsselected from carbon atoms and 1 to 5 heteroatoms; and each heteroatomsbeing O, N or S; and with the proviso that when R⁵ is halogen orhydrogen than R² is other than H; or a pharmaceutically acceptable saltthereof.
 2. (canceled)
 3. The compound according to claim 1, wherein: R⁵is C₁₋₇alkyl, cyano, hydroxy, hydroxy-C₁₋₇alkyl,hydroxy-C₃₋₈cycloalkylalkyl, C₁₋₇alkoxy-C₃₋₈alkyl, —OR⁷, C₆₋₁₀aryl,heteroaryl, heterocyclyl, C₃₋₈cycloalkyl, halo-C₁₋₇alkyl, —NR⁸R⁹,—CH₂—NR⁸—C(O)NR⁸R⁹, —CH₂—NR⁸—SO₂—R¹⁰, —C(O)—R¹⁰, —SO₂R¹⁰, —C(O)—NR⁸R⁹,—SO₂—NR⁸R⁹, —NR⁸C(O)—R¹⁰, —CH₂CN, or —NR⁸—SO₂R¹⁰, or pharmaceuticallyacceptable salt thereof.
 4. The compound according to claim 1, wherein:R¹ is methyl; R² is hydrogen, halogen, —OR⁷ or C₁₋₇alkyl; R³ and R⁴ arehydrogen; R⁵ is hydrogen, C₁₋₇alkyl, halogen, halo-C₁₋₇alkyl, hydroxy,hydroxy-C₁₋₇alkyl, C₁₋₇alkoxy, benzyloxy, C₆₋₁₀aryl, heteroaryl,C₃₋₈cycloalkyl, —CH₂NR⁸SO₂R¹⁰, —SO₂NR⁸R¹⁰ or —NR⁸R⁹; R⁶ is hydrogen orC₁₋₇alkyl; R⁷ is C₁₋₇alkyl, or C₆₋₁₀aryl-C₁₋₇alkyl; and each of R⁸, R⁹and R¹⁰ are independently C₁₋₇alkyl or H, or a pharmaceuticallyacceptable salt thereof.
 5. The compound according to claim 1, wherein:R¹ is methyl; and R² is hydrogen, chloro, methyl, methoxy or —O-benzyl,or a pharmaceutically acceptable salt thereof.
 6. The compound accordingto claim 1, wherein R² is chloro, or a pharmaceutically acceptable saltthereof.
 7. The compound according to claim 1, wherein R² is —OR⁷,wherein R⁷ is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 8. The compound accordingto claim 1, wherein R⁵ is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound according to claim 1 and one or more pharmaceuticallyacceptable carriers.
 10. A combination, in particular a pharmaceuticalcombination, comprising a therapeutically effective amount of thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, and one or more therapeutically active agents selected from anHMG-Co-A reductase inhibitor, an angiotensin II receptor antagonist,angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker(CCB), a dual angiotensin converting enzyme/neutral endopeptidase(ACE/NEP) inhibitor, an endothelin antagonist, a renin inhibitor, adiuretic, an ApoA-I mimic, an anti-diabetic agent, an obesity-reducingagent, an aldosterone receptor blocker, an endothelin receptor blocker,and a CETP inhibitor.
 11. A method of inhibiting aldosterone synthaseactivity in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of the compound according toclaim 1, or a pharmaceutically acceptable salt.
 12. A method of treatinga disorder or a disease in a subject mediated by aldosterone synthase,comprising: administering to the subject a therapeutically effectiveamount of the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 13. A method according to claim 12, wherein thedisorder or the disease is selected from hypokalemia, hypertension,Conn's disease, renal failure, chronic renal failure, restenosis,atherosclerosis, syndrome X, obesity, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction, cardiovascular diseases, renal dysfunction, liver diseases,cerebrovascular diseases, vascular diseases, retinopathy, neuropathy,insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction,migraine headaches, heart failure such as congestive heart failure,arrhythmia, diastolic dysfunction, left ventricular diastolicdysfunction, diastolic heart failure, impaired diastolic filing,systolic dysfunction, ischemia, hypertrophic cardiomyopathy, suddencardiac death, myocardial and vascular fibrosis, impaired arterialcompliance, myocardial necrotic lesions, vascular damage, myocardialinfarction, left ventricular hypertrophy, decreased ejection fraction,cardiac lesions, vascular wall hypertrophy, endothelial thickening, andfibrinoid necrosis of coronary arteries. 14-17. (canceled)